Pyrimidine and Quinazoline Derivatives

ABSTRACT

This invention is concerned with compounds of the formula 
     
       
         
         
             
             
         
       
     
     wherein A, R 1  to R 5  and G are as defined in the description and claims, and pharmaceutically acceptable salts thereof. The invention further relates to pharmaceutical compositions containing such compounds, to a process for their preparation and to their use for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.

PRIORITY TO RELATED APPLICATION(S)

This application is a divisional of U.S. application Ser. No. 11/821,458 filed Jun. 21, 2007, now allowed, which claims the benefit of European Patent Application No. 06116346.5, filed Jun. 29, 2006, which is hereby incorporated by reference in its entirety.

FIELD OF THE INVENTION

The present invention is concerned with novel pyrimidine, quinazoline and purine derivatives, their manufacture, pharmaceutical compositions containing them and their use as medicaments. The active compounds of the present invention are useful in the prevention and/or treatment of diabetes mellitus and other disorders.

In a preferred embodiment, the present invention is concerned with compounds of the formula I

and pharmaceutically acceptable salts thereof.

The compounds of formula I possess pharmaceutical activity, in particular they are modulators of somatostatin receptor activity. More particularly, the compounds are antagonists of the somatostatin receptor subtype 5 (SSTR5).

All documents cited or relied upon below are expressly incorporated herein by reference.

BACKGROUND OF THE INVENTION

Diabetes mellitus is a systemic disease characterized by metabolic disorders involving insulin, carbohydrates, fats and proteins, and disorders in the structure and function of blood vessels. The primary symptom of acute diabetes is hyperglycemia, often accompanied by glucosuria, the presence in urine of large amounts of glucose, and polyuria, the excretion of large volumes of urine. Additional symptoms arise in chronic diabetes, including degeneration of the walls of blood vessels. Although many different human organs are affected by these vascular changes, the eyes and kidneys appear to be the most susceptible. As such, long-standing diabetes mellitus, even when treated with insulin, is a leading cause of blindness.

There are three recognized types of diabetes mellitus. Type I diabetes or insulin dependent diabetes mellitus (IDDM) is typically of juvenile onset; ketosis develops early in life with much more severe symptoms and has a near-certain prospect of later vascular involvement. Control of Type I diabetes is difficult and requires exogenous insulin administration. Type II diabetes or non-insulin dependent diabetes mellitus (NIDDM) is ketosis-resistant, generally develops later in life, is milder and has a more gradual onset. Gestational diabetes is related to type II diabetes and associated with an increased risk of later development of that disease. Type III diabetes is malnutrition-related diabetes.

NIDDM is a condition that poses a major threat to the health of the citizens of the western world. NIDDM accounts for over 85% of diabetes incidence worldwide and about 160 million people are suffering from NIDDM. The incidence is expected to increase considerably within the next decades, especially in developing countries. NIDDM is associated with morbidity and premature mortality resulting from serious complications, e.g., cardiovascular disease (G. C. Weir and J. L. Leahy, Pathogenesis of non-insulin dependent (Type II) diabetes mellitus, in Joslin's Diabetes Mellitus (Eds. C. R. Kahn and G. C. Weir), 13^(th) Edition, 1994, Lea & Febiger, Malvern, Pa., pp. 240-264). NIDDM is characterized by both fasting and post-prandial hyperglycemia resulting from abnormalities in insulin secretion and insulin action (G. C. Weir et al., vide supra).

The hyperglycemia in patients suffering from NIDDM can usually be initially treated by dieting, but eventually most NIDDM patients have to take oral antidiabetic agents and/or insulin injections to normalize their blood glucose levels. The introduction of orally effective hypoglycemic agents was an important development in the treatment of hyperglycemia by lowering blood glucose levels. Currently, the most widely used oral antidiabetic agents are the sulfonylureas, which act by increasing the secretion of insulin from the pancreas (H. E. Lebovitz, Oral antidiabetic agents, in Joslin's Diabetes Mellitus (Eds. C. R. Kahn and G. C. Weir), 13^(th) Edition, 1994, Lea & Febiger, Malvern, Pa., pp. 508-529), the biguanides (e.g., metformin) which act on the liver and periphery by unknown mechanisms (C. J. Bailey, M. R. C. Path and R. C. Turner N. Engl. J. Med. 1996, 334, 574-579) and the thiazolidinediones (e.g., rosiglitazone/Avandia®), which enhance the effects of insulin at peripheral target sites (G. L. Plosker and D. Faulds Drugs 1999, 57, 409-438). These existing therapies which comprise a wide variety of biguanide, sulfonylurea and thiazolidinedione derivatives have been used clinically as hypoglycemic agents. However, all three classes of compound have side effects. The biguanides, for example metformin, are unspecific and in certain cases have been associated with lactic acidosis, and need to be given over a longer period of time, i.e. they are not suitable for acute administration (C. J. Bailey et al., vide supra). The sulfonylureas, though having good hypoglycemic activity, require great care during use because they frequently cause serious hypoglycemia and are most effective over a period of circa ten years. The thiazolidinediones may cause weight gain following chronic administration (G. L. Plosker and D. Faulds, vide supra) and troglitazone has been associated with the occurrence of serious hepatic dysfunction.

Thus, there is a significant and rising need for antidiabetic drugs that have novel mechanisms of action, thereby avoiding side effects produced by known therapies. The hormone somatostatin (SST) is primarily produced in the intestinal tract and in the pancreas. In addition it acts as a neurotransmitter. The hormone is involved through its receptors in the regulation of several other hormones and in immunoregulation. In particular, SST suppresses the secretion of insulin by pancreatic β cells and the secretion of glucagon-like peptide 1 (GLP-1) by L cells. GLP-1 in turn is one of the most potent stimulators of insulin production and secretion and is a trophic factor for β cells. β and L cells express SST receptor subtype 5 (SSTR5) and agonizing this receptor suppresses insulin and GLP-1 secretion in humans and in animal models (e.g., Y. Zambre, Z. Ling, M.-C. Chen, X. Hou, C.-W. Woon, M. Culler, J. E. Taylor, D. H. Coy, C. van Schravendijk, F. Schuit, D. G. Pipeleers and D. L. Eizirik Biochem. Pharmacol. 1999, 57, 1159-1164; S. P. Fagan, A. Azizzadeh, S. Moldovan, M. K. Ray, T. E. Adrian, X. Ding, D. H. Coy and F. C. Brunicardi Surgery 1998, 124, 254-258; M. Norman, S. Moldovan, V. Seghers, X.-P. Wang, F. J. DeMayo and F. C. Brunicardi Ann. Surg. 2002, 235, 767-774; T. A. Tirone, M. A. Norman, S. Moldovan, F. J. DeMayo, X.-P. Wang and F. C. Brunicardi Pancreas 2003, 26, e67-73; M. Z. Strowski, M. Köhler, H. Y. Chen, M. E. Trumbauer, Z. Li, D. Szalkowski, S. Gopal-Truter, J. K. Fisher, J. M. Schaeffer, A. D. Blake, B. B. Zhang and H. A. Wilkinson Mol. Endocrinol. 2003, 17, 93-106).

Consequently, antagonizing the effect of SST would lead to higher plasma insulin concentrations. In patients suffering from impaired glucose tolerance and NIDDM, a higher plasma insulin concentration would moderate the dangerous hyperglycemia and accordingly reduce the risk of tissue damage. If such SSTR5 antagonists are sufficiently selective over the other four SST receptors, little influence is expected on secretion of other hormones. Particularly, selectivity over SST receptor subtype 2 avoids influences on glucagon secretion (K. Cejvan, D. H. Coy and S. Efendic Diabetes 2003, 52, 1176-1181; M. Z. Strowski, R. M. Parmar, A. D. Blake and J. M. Schaeffer Endocrinology 2000, 141, 111-117). Advantageous over established therapies is the dual mechanism of action to increase insulin secretion: directly on pancreatic β cells and indirectly through GLP-1 release from L cells. Additionally, SSTR5 knockout mice demonstrated higher insulin sensitivity than littermates (M. Z. Strowski, M. Köhler et al., vide supra). Therefore, SSTR5 antagonists could have the potential to beneficially influence insulin resistance in patients with NIDDM. In summary, SSTR5 antagonists are expected to beneficially influence NIDDM, the underlying impaired fasting glucose and impaired glucose tolerance, as well as complications of long-standing, insufficiently controlled diabetes mellitus.

GLP-1 is known as an endogenous regulator of gastrointestinal motility and of food intake reducing appetite as shown in laboratory animals, healthy volunteers and patients with NIDDM (E. Näslund, B. Barkeling, N. King, M. Gutniak, J. E. Blundell, J. J. Holst, S. Rössner and P. M. Hellström Int. J. Obes. 1999, 23, 304-311; J.-P. Gutzwiller, B. Göke, J. Drewe, P. Hildebrand, S. Ketterer, D. Handschin, R. Winterhalder, D. Conen and C. Beglinger Gut 1999, 44, 81-88; J.-P. Gutzwiller, J. Drewe, B. Göke, H. Schmidt, B. Rohrer, J. Lareida and C. Beglinger Am. J. Physiol. 1999, 276, R1541-1544; M. D. Turton, D. O'Shea, I. Gunn, S. A. Beak, C. M. Edwards, K. Meeran, S. J. Choi, G. M. Taylor, M. M. Heath, P. D. Lambert, J. P. Wilding, D. M. Smith, M. A. Ghatei, J. Herbert and S. R. Bloom Nature 1996, 379, 69-72; A. Flint, A. Raben, A. Astrup and J. J. Holst J. Clin. Invest. 1998, 101, 515-520; M. B. Toft-Nielsen, S. Madsbad and J. J. Holst Diabetes Care 1999, 22, 1137-1143; P. K. Cheikani, A. C. Haver and R. D. Reidelberger Am. J. Physiol. 2005, 288, R1695-R1706; T. Miki, K. Minami, H. Shinozaki, K. Matsumura, A. Saraya, H. Ikeda, Y. Yamada, J. J. Hoist and S. Seino Diabetes 2005, 54, 1056-1063); thus, elevated GLP-1 will also counteract obesity, a typical condition associated with and leading to NIDDM.

GLP-1 is co-secreted with GLP-2 that is, consequently, also regulated by SST through SSTR5 (L. Hansen, B. Hartmann, T. Bisgaard, H. Mineo, P. N. Jørgensen and J. J. Hoist Am. J. Phys. 2000, 278, E1010-1018). GLP-2 is eterotrophic and beneficial in patients with malabsorption of certain origins, such as short bowel syndrome (D. G. Burrin, B. Stoll and X. Guan Domest. Anim. Endocrinol. 2003, 24, 103-122; K. V. Haderslev, P. B. Jeppesen, B. Hartmann, J. Thulesen, H. A. Sorensen, J. Graff, B. S. Hansen, F. Tofteng, S. S. Poulsen, J. L. Madsen, J. J. Hoist, M. Staun and P. B. Mortensen Scand. J. Gastroenterol. 2002, 37, 392-398; P. B. Jeppesen J. Nutr. 2003, 133, 3721-3724).

Moreover, there is increasing evidence for a role of SST on immune cells and expression of SSTR5 on activated T lymphocytes (T. Talme, J. Ivanoff, M. Hägglund, R. J. J. van Neerven, A. Ivanoff and K. G. Sundqvist Clin. Exp. Immunol. 2001, 125, 71-79; D. Ferone, P. M. van Hagen, C. Semino, V. A. Dalm, A. Barreca, A. Colao, S. W. J. Lamberts, F. Minuto and L. J. Hofland Dig. Liver Dis. 2004, 36, S68-77; C. E. Ghamrawy, C. Rabourdin-Combe and S. Krantic Peptides 1999, 20, 305-311). Consequently, SSTR5 antagonists could also prove valuable in treating diseases characterized by a disturbed immune system, such as inflammatory bowel disease.

SUMMARY OF THE INVENTION

In an embodiment of the present invention, provided is a compound of formula I:

wherein

A is —O— or —NH—;

R¹ is selected from the group consisting of hydrogen, C₁₋₇-alkoxy and halogen; R² is selected from the group consisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, and benzyl; R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, —O—C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl, —NR⁶R⁷, wherein R⁶ and R⁷ independently from each other are hydrogen or C₁₋₇-alkyl, —O—SO₂—R⁸, wherein R⁸ is C₁₋₇-alkyl, and pyrrolyl; R⁴ is selected from the group consisting of hydrogen, hydroxy, C₁₋₇-alkoxy, amino, nitro, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl; or R³ and R⁴ are bonded to each other to form a ring together with the carbon atoms they are attached to and R³ and R⁴ together are —O—C(CH₃)₂—CH═CH—; R⁵ is selected from the group consisting of hydrogen, halogen and C₁₋₇-alkoxy; G is selected from the groups

wherein R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR¹⁷, wherein R¹⁷ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR¹⁸, wherein R¹⁸ is hydrogen or C₁₋₇-alkyl; R¹⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, —C(O)—OR¹⁹, wherein R¹⁹ is hydrogen or C₁₋₇-alkyl, and —NR²⁰R²¹, wherein R²⁰ is hydrogen or C₁₋₇-alkyl and R²¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl and C₁₋₇-alkylcarbonyl, or wherein R²⁰ and R²¹ together with the nitrogen atom they are attached to form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring; R¹¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, amino, —(CH₂)_(m)—C(O)—OR²², wherein m is 0 or 1 and R²² is hydrogen or C₁₋₇-alkyl, phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl, and —(CH₂)_(n)-phenyl, wherein n is 0 or 1 and phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl; R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR²³, wherein R²³ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR²⁴, wherein R²⁴ is hydrogen or C₁₋₇-alkyl; R¹³, R¹⁴, R¹⁵ and R¹⁶ independently from each other are selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, hydroxy, and C₁₋₇-alkoxy; and pharmaceutically acceptable salts thereof.

In another embodiment of the present invention, provided is a process for the manufacture of a compound according to formula I, comprising the steps of: reacting a compound of the general formula

G-X  II

wherein G is as defined in claim 1 and X is halogen, with a compound of the formula

wherein A and R¹ to R⁵ are as defined above, to obtain a compound of the formula

and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt; or, alternatively, reacting a compound of the general formula

wherein G is as defined above, with an aldehyde of the formula

wherein A and R¹ to R⁵ are as defined above, by employing a reducing agent to obtain a compound of the formula

and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt.

In a further embodiment of the present invention, provided is a pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 as well as a pharmaceutically acceptable carrier and/or adjuvant.

In a still another embodiment of the present invention, provided is method for the treatment of diseases which are associated with the modulation of SST receptors subtype 5, comprising the step of administering a therapeutically effective amount of a compound according to claim 1 to a human being or animal in need thereof.

DETAILED DESCRIPTION

It is therefore an embodiment of the present invention to provide selective, directly acting SSTR5 antagonists. Such antagonists are useful as therapeutically active substances, particularly in the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.

In the present description the term “alkyl”, alone or in combination with other groups, refers to a branched or straight-chain monovalent saturated aliphatic hydrocarbon radical of one to twenty carbon atoms, preferably one to sixteen carbon atoms, more preferably one to ten carbon atoms.

The term “lower alkyl” or “C₁₋₇-alkyl”, alone or in combination, signifies a straight-chain or branched-chain alkyl group with 1 to 7 carbon atoms, preferably a straight or branched-chain alkyl group with 1 to 4 carbon atoms. Examples of straight-chain and branched C₁-C₇ alkyl groups are methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, the isomeric pentyls, the isomeric hexyls and the isomeric heptyls, preferably methyl, ethyl, isopropyl, butyl and isobutyl, and most preferred the groups specifically exemplified herein.

The term “lower alkenyl” or “C₂₋₇-alkenyl”, alone or in combination, signifies a straight-chain or branched hydrocarbon residue comprising an olefinic bond and up to 7, preferably up to 6, particularly preferred up to 4 carbon atoms. Examples of alkenyl groups are ethenyl, 1-propenyl, 2-propenyl, isopropenyl, 1-butenyl, 2-butenyl, 3-butenyl and isobutenyl. A preferred example is 2-propenyl (allyl).

The term “cycloalkyl” or “C₃₋₇-cycloalkyl” denotes a saturated carbocyclic group containing from 3 to 7 carbon atoms, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term “alkoxy” refers to the group R′—O—, wherein R' is alkyl. The term “lower alkoxy” or “C₁₋₇-alkoxy” refers to the group R′—O—, wherein R' is lower alkyl and the term “lower alkyl” has the previously given significance. Examples of lower alkoxy groups are e.g., methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, iso-butoxy, sec-butoxy and tert-butoxy, preferably methoxy and ethoxy and most preferred the groups specifically exemplified herein.

The term “lower alkoxyalkyl” or “C₁₋₇-alkoxy-C₁₋₇-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by an alkoxy group as defined above. Among the preferred lower alkoxyalkyl groups are methoxymethyl, methoxyethyl and ethoxymethyl.

The term “lower alkoxyalkoxy” or “C₁₋₇-alkoxy-C₁₋₇-alkoxy” refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by an alkoxy group as defined above. Among the preferred lower alkoxyalkoxy groups are 2-methoxy-ethoxy and 3-methoxy-propoxy.

The term “halogen” refers to fluorine, chlorine, bromine and iodine, with fluorine, chlorine and bromine being preferred.

The term “lower halogenalkyl” or “halogen-C₁₋₇-alkyl” refers to lower alkyl groups as defined above wherein at least one of the hydrogen atoms of the lower alkyl group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro. Among the preferred halogenated lower alkyl groups are trifluoromethyl, difluoromethyl, fluoromethyl, chloromethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl, with trifluoromethyl, 2-fluoroethyl and 2,2,2-trifluoroethyl being especially preferred.

The term “lower halogenalkoxy” or “halogen-C₁₋₇-alkoxy” refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by a halogen atom, preferably fluoro or chloro, most preferably fluoro. Among the preferred halogenated lower alkyl groups are trifluoromethoxy, difluoromethoxy, fluoromethoxy, chloromethoxy, 2-fluoroethoxy and 2,2,2-trifluoroethoxy, with trifluoromethoxy, 2-fluoroethoxy and 2,2,2-trifluoroethoxy being especially preferred.

The term “lower hydroxyalkoxy” or hydroxy-C₁₋₇-alkoxy” refers to lower alkoxy groups as defined above wherein at least one of the hydrogen atoms of the lower alkoxy group is replaced by a hydroxy group. Examples of lower hydroxyalkoxy groups are hydroxymethoxy or hydroxyethoxy.

The term “lower alkylsulfonyl” or “C₁₋₇-alkylsulfonyl” refers to the group R′—C(O)—, wherein R′ is lower alkyl as defined herein before. Examples of lower alkylcarbonyl groups are e.g. acetyl (methylcarbonyl) or ethylcarbonyl.

The term “form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring” refers to a N-heterocyclic ring selected from the group consisting of aziridinyl, azetidinyl, pyrrolidinyl, piperidinyl and azepanyl. A preferred heterocyclic ring is azetidinyl.

The term “pharmaceutically acceptable salts” refers to those salts which retain the biological effectiveness and properties of the free bases or free acids, which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, preferably hydrochloric acid, and organic acids such as acetic acid, propionic acid, glycolic acid, pyruvic acid, oxylic acid, maleic acid, malonic acid, salicylic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition these salts may be prepared form addition of an inorganic base or an organic base to the free acid. Salts derived from an inorganic base include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium salts and the like. Salts derived from organic bases include, but are not limited to salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polymine resins and the like. The compound of formula I can also be present in the form of zwitterions. Particularly preferred pharmaceutically acceptable salts of compounds of formula I are the hydrochloride salts.

The compounds of formula I can also be solvated, e.g., hydrated. The solvation can be effected in the course of the manufacturing process or can take place e.g. as a consequence of hygroscopic properties of an initially anhydrous compound of formula I (hydration). The term “pharmaceutically acceptable salts” also includes physiologically acceptable solvates.

“Isomers” are compounds that have identical molecular formulae but that differ in the nature or the sequence of bonding of their atoms or in the arrangement of their atoms in space. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereoisomers”, and stereoisomers that are non-superimposable mirror images are termed “enantiomers”, or sometimes optical isomers. A carbon atom bonded to four nonidentical substituents is termed a “chiral center”.

In detail, the present invention relates to compounds of the general formula I

wherein

A is —O— or —NH—;

R¹ is selected from the group consisting of hydrogen, C₁₋₇-alkoxy and halogen; R² is selected from the group consisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, and benzyl; R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, —O—C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl, —NR⁶R⁷, wherein R⁶ and R⁷ independently from each other are hydrogen or C₁₋₇-alkyl, —O—SO₂—R⁸, wherein R⁸ is C₁₋₇-alkyl, and pyrrolyl; R⁴ is selected from the group consisting of hydrogen, hydroxy, C₁₋₇-alkoxy, amino, nitro, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl; or R³ and R⁴ are bonded to each other to form a ring together with the carbon atoms they are attached to and R³ and R⁴ together are —O—C(CH₃)₂—CH═CH—; R⁵ is selected from the group consisting of hydrogen, halogen and C₁₋₇-alkoxy; G is selected from the groups

wherein R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR¹⁷, wherein R¹⁷ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR¹⁸, wherein R¹⁸ is hydrogen or C₁₋₇-alkyl; R¹⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, —C(O)—OR¹⁹, wherein R¹⁹ is hydrogen or C₁₋₇-alkyl, and —NR²⁰R²¹, wherein R²⁰ is hydrogen or C₁₋₇-alkyl and R²¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl and C₁₋₇-alkylcarbonyl, or wherein R²⁰ and R²¹ together with the nitrogen atom they are attached to form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring; R¹¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, amino, —(CH₂)_(m)—C(O)—OR²², wherein m is 0 or 1 and R²² is hydrogen or C₁₋₇-alkyl, phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl, and —(CH₂)_(n)-phenyl, wherein n is 0 or 1 and phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl; R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR²³, wherein R²³ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR²⁴, wherein R²⁴ is hydrogen or C₁₋₇-alkyl; R¹³, R¹⁴, R¹⁵ and R¹⁶ independently from each other are selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, hydroxy, and C₁₋₇-alkoxy; and pharmaceutically acceptable salts thereof.

Preferred compounds of formula I of the present invention are those, wherein A is O.

Also preferred are compounds of formula I, wherein A is NH.

Furthermore, compounds of formula I according to the present invention are preferred, wherein R¹ is hydrogen or halogen.

Also preferred are compounds of formula I according to the invention, wherein R² is selected from the group consisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl and C₁₋₇-alkoxy-C₁₋₇-alkyl. Especially preferred are those compounds of formula I, wherein R² is selected from the group consisting of ethyl, propyl, isopropyl, allyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, butyl and isobutyl, with those compounds, wherein R² is ethyl or isopropyl, being most preferred.

Further preferred compounds of formula I according to the present invention are those, wherein R³ is selected from the group consisting of is selected from the group consisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, halogen, —NR⁶R⁷, wherein R⁶ and R⁷ independently from each other are hydrogen or C₁₋₇-alkyl, —O—SO₂—R⁸, wherein R⁸ is C₁₋₇-alkyl, and pyrrolyl.

More preferred are those compounds of formula I, wherein R³ is hydrogen or halogen, with those compounds, wherein R³ is halogen, being especially preferred. Most preferably, R³ is chloro.

Furthermore, compounds of formula I of the present invention are preferred, wherein R⁴ is selected from the group consisting of hydrogen, hydroxy, C₁₋₇-alkoxy, nitro, C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl.

Another group of preferred compounds of formula I according to the present invention are those, wherein R³ and R⁴ are bonded to each other to form a ring together with the carbon atoms they are attached to and R³ and R⁴ together are

—O—C(CH₃)₂₋₀ ^(˜)1=CH—.

These are compounds of the formulae Ia:

Furthermore, compounds of formula I according to the invention are preferred, wherein R⁵ is hydrogen or halogen, with those compounds of formula I, wherein R⁵ is hydrogen, being more preferred.

Especially preferred are compounds of formula I according to the present invention, wherein G is

and wherein R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR¹⁷, wherein R¹⁷ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR¹⁸, wherein R¹⁸ is hydrogen or C₁₋₇-alkyl; R¹⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, —C(O)—OR¹⁹, wherein R¹⁹ is hydrogen or C₁₋₇-alkyl, and —NR²⁰R²¹, wherein R²⁰ is hydrogen or C₁₋₇-alkyl and R²¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl and C₁₋₇-alkylcarbonyl, or wherein R²⁰ and R²¹ together with the nitrogen atom they are attached to form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring; R¹¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, amino, —(CH₂)_(m)—C(O)—OR²², wherein m is 0 or 1 and R²² is hydrogen or C₁₋₇-alkyl, phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl, and —(CH₂)_(n)-phenyl, wherein n is 0 or 1 and phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl.

Within this group, those compounds of formula I are preferred, wherein R⁹ is hydrogen or halogen.

In addition, those compounds of formula I are preferred, wherein R¹⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and —C(O)—OR¹⁹, wherein R¹⁹ is hydrogen or C₁₋₇-alkyl.

Furthermore, compounds of formula I are preferred, wherein R¹¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from C₁₋₇-alkyl and C₁₋₇-alkoxy.

Another group of preferred compounds of formula I according to the invention are those, wherein G is

and wherein R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR²³, wherein R²³ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR²⁴, wherein R²⁴ is hydrogen or C₁₋₇-alkyl; and R¹³, R¹⁴, R¹⁵ and R¹⁶ independently from each other are selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, hydroxy, and C₁₋₇-alkoxy.

Within this group, those compounds are preferred, wherein R¹² is halogen, more preferably R¹¹ is chloro.

A further group of preferred compounds of formula I according to the invention are those, wherein G is selected from the group consisting of

and wherein R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR²³, wherein R²³ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR²⁴, wherein R²⁴ is hydrogen or C₁₋₇-alkyl.

Also within this group, those compounds are preferred, wherein R¹² is halogen, more preferably R¹² is chloro.

Examples of preferred compounds of formula I are the following:

-   (2-chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   2-chloro-N-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-N′-isopropyl-pyrimidine-4,6-diamine, -   (2-chloro-5-methyl-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   N-{2-chloro-6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-pyrimidin-4-yl}-acetamide, -   N⁴-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-6-methyl-pyrimidine-2,4-diamine, -   (2,7-dichloro-quinazolin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-phenyl-quinazolin-4-yl)-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   6-chloro-N⁴-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-pyrimidine-2,4-diamine, -   6-chloro-N⁴-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-pyrimidine-4,5-diamine, -   (6-azetidin-1-yl-2-chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (7-chloro-quinazolin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2,7-dichloro-6-fluoro-quinazolin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dimethoxy-quinazolin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methyl-pyrimidin-4-yl)-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-pyrimidin-4-yl)-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   6-chloro-N⁴-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-pyrimidine-4,5-diamine, -   N-{2-chloro-6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrimidin-4-yl}-acetamide, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-[2-chloro-5-(2-ethyl-4,5-dimethoxy-benzyl)-pyrimidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(7-chloro-quinazolin-4-yl)-amine, -   N⁶-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-9H-purine-2,6-diamine, -   6-chloro-N⁴-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-pyrimidine-4,5-diamine, -   (6-chloro-5-phenoxy-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   (6-chloro-5-o-tolyloxy-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [6-chloro-5-(2-ethoxy-phenoxy)-pyrimidin-4-yl]-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [6-chloro-5-(4-methoxy-phenoxy)-pyrimidin-4-yl]-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [6-chloro-5-(2-methoxy-benzyl)-pyrimidin-4-yl]-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [6-chloro-5-(2-trifluoromethyl-benzyl)-pyrimidin-4-yl]-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-amine, -   (2-chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-pyrimidin-4-yl)-amine, -   4-[4-(2-chloro-pyrimidin-4-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenol, -   (2-chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-pyrimidin-4-yl)-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-amine, -   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-pyrimidin-4-yl)-amine, -   (2-chloro-pyrimidin-4-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine, -   3-[4-(2-chloro-pyrimidin-4-ylamino)-piperidin-1-ylmethyl]-5-isopropoxy-phenol, -   (2-chloro-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-iodo-5-methoxymethoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(2-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-pyrimidin-4-yl)-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-6-methyl-pyrimidin-4-yl)-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3,4-diethoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-{1-[4-methoxy-3-(2,2,2-trifluoro-ethoxy)-benzyl]-piperidin-4-yl}-amine, -   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-6-methyl-pyrimidin-4-yl)-amine, -   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-6-methyl-pyrimidin-4-yl)-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-6-methyl-pyrimidin-4-yl)-amine, -   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-6-methyl-pyrimidin-4-yl)-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2,6-dichloro-pyrimidin-4-yl)-amine, -   4-[4-(2,6-dichloro-pyrimidin-4-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenol, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-amine, -   (2,6-dichloro-pyrimidin-4-yl)-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-amine, -   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-(2,6-dichloro-pyrimidin-4-yl)-amine, -   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2,6-dichloro-pyrimidin-4-yl)-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine, -   3-[4-(2,6-dichloro-pyrimidin-4-ylamino)-piperidin-1-ylmethyl]-5-isopropoxy-phenol, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2,6-dichloro-pyrimidin-4-yl)-amine, -   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2,6-dichloro-pyrimidin-4-yl)-amine, -   (2,6-dichloro-pyrimidin-4-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine, -   4-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol,     4-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3-ethoxy-4-hydroxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-methoxy-6-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-ylamino]-pyrimidin-2-ol, -   4-[1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   4-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-6-methoxy-pyrimidin-2-ol, -   2-chloro-6-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-ylamino}-pyrimidine-4-carboxylic     acid methyl ester, -   6-[1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-ylamino]-2-chloro-pyrimidine-4-carboxylic     acid methyl ester, -   6-[1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-2-chloro-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-hydroxy-5-isopropoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   6-[1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-2-chloro-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-ethoxy-4-iodo-5-methoxymethoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(2-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-ethoxy-4-methoxy-5-nitro-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   2-chloro-6-[1-(3-ethylamino-4-methoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   N-{2-chloro-6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrimidin-4-yl}-acetamide, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3,4-diethoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-{1-[4-methoxy-3-(2,2,2-trifluoro-ethoxy)-benzyl]-piperidin-4-yl}-amine, -   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   (2-chloro-5-fluoro-pyrimidin-4-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine, -   [1-(2-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   4-[4-(2-chloro-5-methoxy-pyrimidin-4-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenol, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl]-amine, -   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   3-[4-(2-chloro-5-methoxy-pyrimidin-4-ylamino)-piperidin-1-ylmethyl]-5-isopropoxy-phenol, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   [1-(4-bromo-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   [1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine, -   [1-(2-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-amine, -   4-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenol, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-{1-[3-ethoxy-4-(1-ethyl-propoxy)-benzyl]-piperidin-4-yl}-amine, -   methanesulfonic acid     4-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenyl     ester, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-{1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-amine, -   [1-(3-allyloxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-amine, -   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine, -   3-[4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-piperidin-1-ylmethyl]-5-isopropoxy-phenol, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(3-benzyloxy-5-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine, -   [1-(2-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-amine, -   {2,4-dichloro-6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-pyrimidin-5-yl}-acetic     acid ethyl ester, -   {2,4-dichloro-6-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-ylamino]-pyrimidin-5-yl}-acetic     acid ethyl ester, -   {2,4-dichloro-6-[1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-pyrimidin-5-yl}-acetic     acid ethyl ester, -   {4-[1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-ylamino]-2,6-dichloro-pyrimidin-5-yl}-acetic     acid ethyl ester, -   {2,4-dichloro-6-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-ylamino]-pyrimidin-5-yl}-acetic     acid ethyl ester, -   [1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   {1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   [1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   [1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-(2,5,6-trichloro-pyrimidin-4-yl)-amine, -   (7-chloro-quinazolin-4-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine, -   (7-chloro-quinazolin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   4-[4-(7-chloro-quinazolin-4-ylamino)-piperidin-1-ylmethyl]-2-ethoxy-phenol, -   (7-chloro-quinazolin-4-yl)-[1-(3,5-diethoxy-benzyl)-piperidin-4-yl]-amine, -   (7-chloro-quinazolin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   (7-chloro-quinazolin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(7-chloro-quinazolin-4-yl)-amine, -   [1-(4-amino-3,5-diethoxy-benzyl)-piperidin-4-yl]-(7-chloro-quinazolin-4-yl)-amine, -   (7-chloro-quinazolin-4-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dimethoxy-quinazolin-4-yl)-[1-(3-ethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dimethoxy-quinazolin-4-yl)-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dimethoxy-quinazolin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dimethoxy-quinazolin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-6,7-dimethoxy-quinazolin-4-yl)-[1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-amine, -   [1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   2-ethoxy-4-[4-(9H-purin-6-ylamino)-piperidin-1-ylmethyl]-phenol, -   [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(3-ethoxy-4-isopropoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(4-methoxy-3-propoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   {1-[3-(2-fluoro-ethoxy)-4-methoxy-benzyl]-piperidin-4-yl}-(9H-purin-6-yl)-amine, -   [1-(3-butoxy-4-methoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(3-isobutoxy-4-methoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(8-ethoxy-2,2-dimethyl-2H-chromen-6-ylmethyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   [1-(3,5-diethoxy-4-pyrrol-1-yl-benzyl)-piperidin-4-yl]-(9H-purin-6-yl)-amine, -   6-[1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-2,4-dicarboxylic     acid,     and pharmaceutically acceptable salts thereof.

Especially preferred are the following compounds of formula I of the present invention:

-   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-pyrimidin-4-yl)-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(7-chloro-quinazolin-4-yl)-amine, -   (6-chloro-5-o-tolyloxy-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   (2-chloro-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-6-methyl-pyrimidin-4-yl)-amine, -   (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2,6-dichloro-pyrimidin-4-yl)-amine, -   2-chloro-6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic     acid methyl ester, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, -   (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, -   [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, -   (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, -   (7-chloro-quinazolin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine,     and pharmaceutically acceptable salts thereof.

Furthermore, the pharmaceutically acceptable salts of the compounds of formula I individually constitute preferred embodiments of the present invention.

Compounds of formula I can have one or more asymmetric carbon atoms and can exist in the form of optically pure enantiomers, mixtures of enantiomers such as, for example, racemates, optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates. The optically active forms can be obtained for example by resolution of the racemates, by asymmetric synthesis or asymmetric chromatography (chromatography with a chiral adsorbens or eluant). The invention embraces all of these forms.

It will be appreciated, that the compounds of general formula I in this invention may be derivatized at functional groups to provide derivatives which are capable of conversion back to the parent compound in vivo. Physiologically acceptable and metabolically labile derivatives, which are capable of producing the parent compounds of general formula I in vivo are also within the scope of this invention.

A further aspect of the present invention is the process for the manufacture of compounds of formula I as defined above, which process comprises reacting a compound of the general formula

G-X  II

wherein G is as defined herein before and X is halogen, with a compound of the formula

wherein A and R¹ to R⁵ are as defined herein before, to obtain a compound of the formula

and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt; or, alternatively, reacting a compound of the general formula

wherein G is as defined herein before, with an aldehyde of the formula

wherein A and R¹ to R⁵ are as defined herein before, by employing a reducing agent to obtain a compound of the formula

and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt.

The invention further relates to compounds of formula I as defined above, when manufactured according to a process as defined above.

Suitable reducing agents are preferably selected from the group consisting of pyridine-BH₃ complex, NaBH(OAc)₃ and NaCNBH₃. The reaction can be carried out under acidic conditions by using an acid such as acetic acid or formic acid or an Lewis acid (e.g., Ti(iPrO)₄, ZnCl₂) or under basic conditions (no additive) in a suitable solvent such as dichloromethane, dichloroethane or ethanol (or mixtures thereof) at ambient or elevated temperatures using conventional heating or heating by microwave irradiation.

As described above, the compounds of formula I of the present invention can be used as medicaments for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.

“Diseases which are associated with the modulation of SST receptors subtype 5” are such diseases as diabetes mellitus, particularly type II diabetes mellitus, impaired fasting glucose, impaired glucose tolerance, micro- and macrovascular diabetic complications, posttransplantation diabetes mellitus in patients having type I diabetes mellitus, gestational diabetes, obesity, inflammatory bowel diseases such as Crohn's disease or ulcerative colitis, malabsorption, autoimmune diseases such as rheumatoid arthritis, osteoarthritis, psoriasis and other skin disorder, and immunodeficiences. Microvascular diabetic complications include diabetic nephropathy and diabetic retinopathy, whereas macrovascular diabetes-associated complications lead to an increased risk for myocardial infarction, stroke and limb amputations.

The use as medicament for the treatment and/or prevention of diabetes mellitus, particularly type II diabetes mellitus, impaired fasting glucose or impaired glucose tolerance is preferred.

The invention therefore also relates to pharmaceutical compositions comprising a compound as defined above and a pharmaceutically acceptable carrier and/or adjuvant.

Further, the invention relates to compounds as defined above for use as therapeutically active substances, particularly as therapeutic active substances for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.

In another embodiment, the invention relates to a method for the treatment and/or prevention of diseases which are which are associated with the modulation of SST receptors subtype 5, which method comprises administering a compound of formula Ito a human or animal. The method for the treatment and/or prevention of diabetes mellitus, particularly type II diabetes mellitus, impaired fasting glucose or impaired glucose tolerance, is most preferred.

The invention further relates to the use of compounds as defined above for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5.

In addition, the invention relates to the use of compounds as defined above for the preparation of medicaments for the treatment and/or prevention of diseases which are associated with the modulation of SST receptors subtype 5. Preferred examples of such diseases are diabetes mellitus, particularly type II diabetes mellitus, impaired fasting glucose or impaired glucose tolerance.

The compounds of formula I can be manufactured by the methods given below, by the methods given in the examples or by analogous methods. Appropriate reaction conditions for the individual reaction steps are standard reactions and are known to a person skilled in the art. Starting materials are either commercially available or can be prepared by methods analogous to the methods given below, by methods described in references cited in the text or in the examples, or by methods known in the art.

The synthesis of compounds with the general structure I, particularly compounds according to formula Ia to IId, are described in Schemes 1 to 11.

The synthesis of compounds of the general formula I, particularly compounds according to formula Ib can be accomplished according to Scheme 1.

Reductive N-alkylation of suitably protected piperidines (for protecting groups see Protective Groups in Organic Synthesis, T. W. Greene, Wiley-Interscience 1999) of formula I with aldehydes 2 in the presence of a reducing agent such as pyridine-BH₃ complex, NaBH(OAc)₃ or NaCNBH₃ under acidic conditions (e.g., acetic acid, formic acid), by using a Lewis acid (e.g., Ti(iPrO)₄, ZnCl₂) or under buffered conditions, e.g., in the presence of acetic acid and a tertiary amine like N-ethyl-diisopropylamine or triethylamine in a suitable solvent such as dichloromethane, dichloroethane, ethanol or isopropanol (or mixtures thereof) at ambient or elevated temperatures using conventional heating or heating by microwave irradiation provide piperidines of general formula 3 (Scheme 1, step a). The piperidines of formula I may thereby used either as a salt, e.g., hydrochloride or hydrobromide salt, or as the corresponding free amine. The alkyloxycarbonyl protecting group present in compounds 3 can be removed, using e.g., 48% aqueous hydrogen bromide or 37% aqueous hydrochloric acid as reagent preferably at elevated temperatures to remove an ethyl carbamate or using trifluoroacetic acid or hydrochloric acid in a solvent like dichloromethane, dioxane or THF preferable at room temperature to remove a tert-butyloxycarbonyl (BOC)-protective group (see Protective Groups in Organic Synthesis, T. W. Greene, Wiley-Interscience 1999), yielding 4-amino piperidines of formula 4 (Scheme 1, step b).

Target compounds of formula I can be synthesized by nucleophilic replacement reaction of 4-amino piperidines of formula 4 and a variety of pyrimidines, quinazolines or purines of general structure 5 at room or elevated temperatures (Scheme 1, step c), whereby X is a suitable leaving group such as fluorine, chlorine, bromine or methyl sulfone. Thereby heating can be achieved conventionally or by microwave irradiation using a suitable microwave irradiation apparatus. Furthermore the reaction can be conducted in the presence of or without solvent (typically an aprotic polar solvent such as DMF (N,N-dimethylformamide), DMAc (dimethylacetamide), NMP (N-methylpyrrolidon), ethylene glycol, acetonitrile or THF) and in the presence of or without a tertiary amine base such as N-ethyl diisopropylamine, triethylamine or pyridine and in the presence with or without copper(I) bromide or copper(I) iodide. The starting materials and some of the intermediates of general structure 5 (e.g., 4-chloro-pyrimidines, 2,4-dichloro-pyrimidines, 4-chloro-quinazolines, 2,4-dichloro-quinazolines or 6-chloro-9H-purines) are known compounds and are commercially available or can be prepared by numerous methods using conventional reaction procedures generally known in the art. The 4-amino piperidines of formula 4 may thereby used either as a salt, e.g., hydrochloride or hydrobromide salt, or as the corresponding free amine. Alternatively the nucleophilic displacement reaction can be conducted under basic conditions by using K₂CO₃, KOH, NaOCH₃, KOtert-Bu or in particular by using NaH. If the coupling reaction is conducted with 2,4-dihalo-pyrimidines or 2,4-dihalo-quinazolines, preferentially with 2,4-dichloro-pyrimidines, regioisomeric coupling products might be obtained, which can be separated by conventional chromatographic methods. In cases where nucleophilic substitution leads to regioisomeric products the regiochemistry of target structures I was unambiguously established by means of nuclear magnetic resonance spectroscopy employing 1D-NOE difference, 2D-NOESY and/or ¹³C/¹HMBC experiments. In many cases ¹H NMR spectra revealed the presence of tautomeric structures at room temperature (rt).

Alternatively target structures I can be achieved using Pd(0)-catalyzed amination reactions of 4-halo-pyrimidines, 2,4-dihalo-pyrimidines, 4-halo-quinazolines, 2,4-dihalo-quinazolines or 6-halo-9H-purines of formula 5 with 4-amino piperidines 4 (e.g., Buchwald-Hartwig coupling; see (a) J. P. Wolfe, S. Wagaw and S. L. Buchwald J. Am. Chem. Soc. 1996, 118, 7215-7216; (b) J. P. Wolfe and S. L. Buchwald Tetrahedron Lett. 1997, 38, 6359-6362; (c) J. P. Wolfe, S. Wagaw, J.-F. Marcoux and S. L. Buchwald Acc. Chem. Res. 1998, 31, 805-818; (d) B. H. Yang and S. L. Buchwald J. Organomet. Chem. 1999, 576, 125-146; (e) J. F. Hartwig Angew. Chem. Int. Ed. 1998, 37, 2046-2067). Thereby halo-substituted heterocyclic compounds 5 are reacted with amines 4 under an inert atmosphere such as argon or nitrogen in the presence of a palladium catalyst such as tris(dibenzylideneacetone)dipalladium(0) (Pd₂(dba)₃) or palladium(II) acetate (Pd(COOCH₃)₂), a phosphine ligand like triphenylphosphine, rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (rac-BINAP) or (R)-(−)-1-[(S)-2-(dicyclohexylphosphino)ferrocenyl]ethyldi-tert-butylphosphine (Josiphos; see Q. Shen, S. Shekhar, J. P. Stambuli and J. F. Hartwig Angew. Chem. Int. Ed. 2005, 44, 1371-1375) and a base such as Cs₂CO₃ or KOtert-Bu in a solvent like toluene, ethanol or water or mixtures thereof (Scheme 1, step c). Said C—N formation reaction may be conducted at room temperature or in order to enhance the rate of conversion at elevated temperatures, whereby heating might be achieved conventionally or by microwave irradiation (see also Palladium(0) Complexes in Organic Chemistry, in Organometallics in Synthesis (Ed. M. Schlosser), Chapter 4, 2^(nd) Edition, 2002, John Wiley & Sons, Ltd, Chichester, UK).

Target structures of formula I can also be accomplished employing an inverted reaction sequence, namely by first coupling halo-substituted heterocycles 5 with alkyloxycarbonyl protected amine 6 (Scheme 2, step a). The protection group of piperidines 7 are then removed yielding the secondary amines 8 (Scheme 2, step b), which undergo reductive N-alkylation to target structures I (Scheme 2, step c). In contrast to the strategy outlined in Scheme 1, where the point of diversification is the heteroaryl moiety, this synthetic route is of particular interest if the variation of the benzyl moiety is aimed for in a rapid and parallel fashion.

Target compounds of formula I might also be synthesized by direct alkylation of piperidines 8 with suitable halides, mesylates, tosylates or alcohols containing any other suitable leaving group of structure 9 in solvents such as N,N-dimethylformamide, dichloromethane, dichloroethane or acetone at ambient or elevated temperatures using conventional heating or heating by microwave irradiation with the addition of a suitable tertiary amine base (e.g., N-ethyl diisopropylamine, triethylamine) or an inorganic base (e.g., Cs₂CO₃, K₂CO₃) or by analogous alkylation reactions (Scheme 3, step a). Alternatively target structures of formula I might be accessible by Mitsunobu reaction (D. L. Hughes, The Mitsunobu Reaction, in Organic Reactions, Volume 42, 1992, John Wiley & Sons, New York; pp. 335-656) applying alcohols 10 activated by a mixture of triphenylphosphine and diethyl- or di-tert-butyl-azadicarboxylate (Scheme 3, step b).

Synthesis of Pyrimidine and Quinazoline Intermediates

The starting materials of general formula IIa are either commercially available, known in the literature or can be obtained on application of classical methods of pyrimidine synthesis and subsequent functional group conversion such as by condensation of β-keto carboxylic acids 11 (malonic esters) with urea (12) as illustrated in step a of Scheme 4 (e.g., see Y.-Z. Kim, J.-C. Lim, J.-H. Yeo, C.-S. Bang, W.-S. Kim, S.-S. Kim, Y.-M. Woo, D.-H. Yang, H. Oh and K. Nahm J. Med. Chem. 1994, 37, 3828-3833). Halogenation of the pyrimidine intermediates 13 to provide compounds of general formula IIa can be accomplished in refluxing POCl₃ or PCl₃/PCl₅ (Scheme 4, step b; see also H. Krauch and W. Kunz, Reaktionen der organischen Chemie, 6., neubearbeitete Auflage, 1997, Hüthig GmbH, Heidelberg, Deutschland). The corresponding bromo derivatives of IIa are accessible when POBr₃ is used instead of POCl₃ as the halogenation agent. Furthermore, the halogenation step can be conducted in the presence or absence of catalytic amounts of N,N-dimethylaniline. All of these reactions are standard operations and can be carried out under conditions which are usual for such reactions and which are familiar to a person skilled in the art.

Alternatively, the preparation of target structures IIa can be achieved by condensation of β-keto carboxylic acids 11 (malonic esters) with guanidine (14) yielding 2-amino pyrimidines 15 (Traube synthesis; see A. R. Katritzky and T. I. Yousaf Canad. J. Chem. 1986, 64, 2087-2093; Scheme 5, step a). The 4-hydroxy group in pyrimidines 15 can then be converted to chloride employing standard halogenation conditions such as refluxing POCl₃ or PCl₃/PCl₅ (Scheme 5, step b). The 2-amino group in pyrimidines 16 can then be transformed to chloride employing standard Sandmeyer reaction conditions such as diazotization with sodium nitrite in the presence of hydrochloric acid at lower temperatures preferentially between −10° C. and 10° C. (Scheme 5, step c).

According to Scheme 6 target structures IIa can also be obtained by halogenation of uracils 17 with POCl₃ or PCl₃/PCl₅ (step a). This route is particularly amenable to pyrimidines with R¹=R²=halogenes, such as fluoride or chloride.

4,6-Dichloro-5-phenoxy-pyrimidine intermediates of general structure IIb can be obtained by the reaction sequence sketched hereinafter (R²¹, R²², R²³, R²⁴ and R²⁵ independently from each other are selected from the group consisting of hydrogen, C₁₋₇-alkyl and C₁₋₇-alkoxy). Alkylation of phenols 18 with 2-chloro-malonic acid diethyl ester (diethyl chloromalonate, 19) yields compounds 20 (Scheme 7, step a) which are condensed under basic conditions (e.g., sodium ethanolate) with formamidine acetate or homologous compounds 21 such as acetamidine acetate in a solvent like ethanol providing phenoxy pyrimidinedione derivatives 22 (Scheme 7, step b). Chlorination with POCl₃ or PCl₃/PCl₃ provides then compounds IIb (Scheme 7, step c).

Synthesis of 5-benzyl-4,6-dichloro-pyrimidine intermediates IIc containing a carbon linker (Y═C) between the phenyl and the pyrimidine moiety can be achieved by a reaction sequence outlined in Scheme 8. Alkylation of benzylhalides 23 with malonic acid diethyl ester (24) provides compounds 25 (Scheme 8, step a), which alternatively can also be obtained by Knoevenagel condensation of benzaldehydes 26 with 24 (Scheme 8, step b). Conversion under basic conditions (e.g., sodium ethanolate) with formamidine acetate or homologous compounds 21 such as acetamidine acetate in a solvent like ethanol gives then access to the benzyl pyrimidinediones 27 (Scheme 8, step c). Chlorination of 27 with POCl₃ or PCl₃/PCl₃ provides then intermediates IIc (Scheme 8, step d).

There are myriads of references known in the art teaching methods useful for the preparation of pyrimidines. The reader is referred to (a) D. J. Brown, The Pyrimidines, in The Chemistry of Heterocyclic Compounds (Ed. A. Weissberger), Volume 16, 1962, Interscience Publishers, New York; (b) D. J. Brown, The Pyrimidines, in The Chemistry of Heterocyclic Compounds (Eds. A. Weissberger and E. C. Taylor), Volume 16, Supplement I, 1970, Interscience Publishers, New York; (c) D. J. Brown, R. F. Evans, W. B. Cowden and M. D. Fenn, The Pyrimidines, in The Chemistry of Heterocyclic Compounds (Eds. A. Weissberger and E. C. Taylor), Volume 16, Supplement II, 1985, Interscience Publishers, New York; (d) D. J. Brown, The Pyrimidines, in The Chemistry of Heterocyclic Compounds (Eds. A. Weissberger and E. C. Taylor), Volume 52, Supplement I, 1994, Interscience Publishers, New York; (e) L. A. Paquette, Principles of Modern Heterocyclic Chemistry, 1968, W. A. Benjamin, Inc., New York (uracil synthesis pp. 313-315; pyrimidine synthesis pp. 313-316); (f) Comprehensive Organic Synthesis (Eds. B. M. Trost and I. Fleming), 1992, Pergamon Press, Oxford, UK.

Further syntheses of pyrimidines of formula IIa-c are described in the examples.

The starting materials of general formula IId are either commercially available, known in the literature or can be obtained on application of classical methods of quinazoline synthesis. A classical route for the synthesis of quinazolines IId is outlined in Scheme 9. Condensation of anthranilic acids 28 and sodium or potassium cyanate in water and glacial acetic acid furnishes quinazoline-2,4-diols 29 (step a; see F. H. S. Curd, J. K. Landquist and F. L. Rose J. Chem. Soc. 1948, 1759-1766), which upon subsequent functional group conversion, e.g., treatment at elevated temperatures with phosphorus oxychloride in chloroform or neat and in the presence or absence of N,N-dimethylaniline as a catalyst, provide 2,4-dichloroquinazolines IId (step b). Alternatively, the cyclisation of anthranilic acids 28 to quinazoline-2,4-diols 29 can be achieved using urea preferably at elevated temperatures with or without solvent (see (a) E. H. Huntress and J. V. K. Gladding J. Am. Chem. Soc. 1942, 64, 2544-2649; (b) E. Cuny, F. W. Lichtenthaler and A. Moser Tetrahedron Lett. 1980, 21, 3029-3032).

For the synthesis of 4-chloroquinazolines IIe anthranilic acids 28 are condensed preferentially neat with formamide at elevated temperatures using conventional heating or heating by microwave irradiation to yield directly quinazolin-4-ols 30 as outlined in Scheme 10 (step a; see (a) M. M. Endicott, E. Wick, M. L. Mercury and M. L. Sherrill J. Am. Chem. Soc. 1946, 68, 1299-1301; (b) C. C. Price, N. J. Leonard and D. Y. Curtin J. Am. Chem. Soc. 1946, 68, 1305-1306). Chlorination of 30 with POCl₃ or PCl₃/PCl₃ gives then straight access to the desired intermediates IIe (Scheme 10, step b).

Most of the synthetic routes outlined in Scheme 4 to Scheme 10 are amenable to both solution and solid-phase synthesis (see J. T. Bork, J. W. Lee and Y.-T. Chang QSAR Comb. Sci. 2004, 23, 245-260).

The two halogen groups in pyrimidines and quinazolines IIa-d exhibit different chemical reactivity, with the chloride at the C2 position being inherently less reactive. This allows the sequential replacement of first the C4 and second the C2 chloride atom, e.g., by nucleophilic substitution reactions with amines or aliphatic or aromatic alcohols or by Pd(0)-catalyzed Suzuki, Buchwald-Hartwig or Stille-type coupling reactions, providing access to a large number of differently substituted intermediates of general structure IIa-d. The regiochemistry of target structures IIa-d was unambiguously established by means of nuclear magnetic resonance spectroscopy employing 1D-NOE difference, 2D-NOESY and/or ¹³C/¹HMBC experiments.

Further syntheses of quinazolines of formula IId are described in the examples.

Synthesis of Aldehyde Intermediates

The requisite aldehyde partners are either commercially available or can be derived by alkylation with alkyl halides, alkyl mesylates, alkyl tosylates or alcohols containing any other suitable leaving group in a polar solvent such as DMF or acetone and a suitable base (e.g., Cs₂CO₃, K₂CO₃) at room temperature or elevated temperatures, by Mitsunobu reaction with alcohols activated by a mixture of triphenylphosphine and diethylazadicarboxylate, or by analogous alkylation of the phenolic carboxylic esters or acids of formula 31 (Scheme 10, step a). Reduction of the esters of formula 32 by a suitable reducing agent (e.g., diisobutylaluminium hydride at low temperature, with LiAlH₄ at elevated or ambient temperature) in a solvent such as THF provides the corresponding benzylalcohols of formula 33 (Scheme 11, step b). These can then be oxidized to the aldehydes of formula 34, preferably with activated MnO₂ as oxidant in dichloromethane (Scheme 11, step c).

Alternatively the introduction of the side-chain can be accomplished by direct alkylation (sequential for unsymmetrical compounds) of the phenolic benzaldehydes of formula 35 providing the desired compounds of formula 34 directly (Scheme 11, step d).

A further well-established route towards the synthesis of benzylaldehydes of formula 37 consists in the reduction of the corresponding benzonitriles of formula 36 by a suitable reducing agent such as diisobutylaluminium hydride at low temperature in a non-protic polar solvent (e.g., THF; Scheme 11, step e).

Additional syntheses of aldehydes of formula III are described in the examples.

As described hereinbefore, it has been found that the compounds of formula I possess pharmaceutical activity, in particular they are modulators of somatostatin receptor activity. More particularly, the compounds of the present invention have been found to be antagonists of the somatostatin receptor subtype 5 (SSTR5).

The following tests were carried out in order to determine the activity of the compounds of formula I.

A CHO cell line stably transfected with a plasmid encoding the human subtype 5 somatostatin receptor (GenBank accession number D16827) was obtained from Euroscreen. Cells were cultured and used for binding and functional assays.

Membranes of these cells were prepared by sonication in the presence of protease inhibitors and subsequent fractionating centrifugation. The protein concentration in the membrane preparation was determined using a commercial kit (BCA kit, Pierce, USA). Membranes were stored at ±80° C. until use. After thawing, membranes were diluted in assay buffer (50 mM Tris-HCl at pH 7.4, 5 mM MgCl₂ and 0.20% BSA) and subjected to dounce homogenization.

For binding studies, 0.1 mL membrane suspension, corresponding to app. 6×10⁻¹⁵ mol receptor, was incubated for 1 h at room temperature with 0.05 nM ¹²⁵I-labeled tracer (11-Tyr somatostatin-14, Perkin-Elmer) and either test compounds in varying concentrations or, for the determination of non-specific binding, 0.001 mM non-labeled somatostatin-14. The incubation was stopped by filtration through GF/B glassfiber filters and washing with ice-cold wash buffer (50 mM Tris-HCl at pH 7.4). The bound radioactivity was measured after application of a scintillation cocktail (Microscint 40) and expressed as disintegrations per minute (dpm).

The receptor concentration was determined in a prior saturation experiment where a fixed, arbitrary amount of membranes was incubated with a concentration range of radio-labeled tracer. This allows estimating the total number of specific binding sites per amount of protein (i.e., B_(max)), typically between 1 and 5 pmol/mg.

The concentration of the test compound required to result in half maximal inhibition of binding of the radio-labeled tracer (IC₅₀) was estimated from a concentration-versus-dpm graph. The binding affinity (K_(i)) was calculated from the IC₅₀ by applying the Cheng-Prussoff equation for single binding sites.

For functional experiments, 50'000 cells were incubated in Krebs Ringer HEPES buffer (115 mM NaCl, 4.7 mM KCl, 2.56 mM CaCl₂, 1.2 mM KH₂PO₄, 1.2 mM MgSO₄, 20 mM NaHCO₃ and 16 mM HEPES, adjusted to pH 7.4) supplemented with 1 mM IBMX and 0.1% BSA, then stimulated with 0.004 mM forskolin. Simultaneously with forskolin, test compounds in varying concentrations were applied. Cells were then incubated for 20 min at 37° C. and 5% CO₂. Subsequently, cells were lysed and cAMP concentration measured using a fluorescence-based commercial kit according to the manufacturer (HitHunter cAMP, DiscoverX).

The concentration of the test compound to induce a half maximal effect (i.e., EC₅₀) as well as the efficacy as compared to 0.15 nM somatostatin-14 were determined from concentration-versus-fluorescence (arbitrary units) graphs. For the determination of potential antagonism, 0.15 nM somatostatin-14 was applied together with the test compounds and the concentration of the test compounds to half maximally reverse the effect of somatostatin-14 (i.e., IC₅₀) were deduced from concentration-versus-fluorescence graphs.

The compounds of the present invention exhibit K_(i) values of 0.1 nM to 10 μM, preferably K_(i) values of 1 nM to 500 nM and more preferably 0.1 nM to 100 nM for human subtype 5 somatostatin receptor. The following table shows measured values for selected compounds of the present invention.

SSTR5 K_(i) (nmol/l) Example 15 383 Example 23 2 Example 147 78

The compounds of formula I and their pharmaceutically acceptable salts and esters can be used as medicaments, e.g., in the form of pharmaceutical preparations for enteral, parenteral or topical administration. They can be administered, for example, perorally, e.g., in the form of tablets, coated tablets, dragées, hard and soft gelatine capsules, solutions, emulsions or suspensions, rectally, e.g., in the form of suppositories, parenterally, e.g., in the form of injection solutions or infusion solutions, or topically, e.g., in the form of ointments, creams or oils.

The production of the pharmaceutical preparations can be effected in a manner which will be familiar to any person skilled in the art by bringing the described compounds of formula (I) and their pharmaceutically acceptable, into a galenical administration form together with suitable, non-toxic, inert, therapeutically compatible solid or liquid carrier materials and, if desired, usual pharmaceutical adjuvants.

Suitable carrier materials are not only inorganic carrier materials, but also organic carrier materials. Thus, for example, lactose, corn starch or derivatives thereof, talc, stearic acid or its salts can be used as carrier materials for tablets, coated tablets, dragées and hard gelatine capsules. Suitable carrier materials for soft gelatine capsules are, for example, vegetable oils, waxes, fats and semi-solid and liquid polyols (depending on the nature of the active ingredient no carriers are, however, required in the case of soft gelatine capsules). Suitable carrier materials for the production of solutions and syrups are, for example, water, polyols, sucrose, invert sugar and the like. Suitable carrier materials for injection solutions are, for example, water, alcohols, polyols, glycerol and vegetable oils. Suitable carrier materials for suppositories are, for example, natural or hardened oils, waxes, fats and semi-liquid or liquid polyols. Suitable carrier materials for topical preparations are glycerides, semi-synthetic and synthetic glycerides, hydrogenated oils, liquid waxes, liquid paraffins, liquid fatty alcohols, sterols, polyethylene glycols and cellulose derivatives.

Usual stabilizers, preservatives, wetting and emulsifying agents, consistency-improving agents, flavor-improving agents, salts for varying the osmotic pressure, buffer substances, solubilizers, colorants and masking agents and antioxidants come into consideration as pharmaceutical adjuvants.

The dosage of the compounds of formula (I) can vary within wide limits depending on the disease to be controlled, the age and the individual condition of the patient and the mode of administration, and will, of course, be fitted to the individual requirements in each particular case. For adult patients a daily dosage of about 1 mg to about 1000 mg, especially about 1 mg to about 100 mg, comes into consideration. Depending on the dosage it is convenient to administer the daily dosage in several dosage units.

The pharmaceutical preparations conveniently contain about 0.1-500 mg, preferably 0.5-100 mg, of a compound of formula I.

The present invention will be further explained by reference to the following illustrative examples. They are, however, not intended to limit its scope in any manner.

EXAMPLES Abbreviations

Ar=argon, DMAc=dimethylacetamide, DMF=N,N-dimethylformamide, DMSO=dimethyl sulfoxide, EI=electron impact (ionization), ESI=electron spray ionisation, HPLC=high performance liquid chromatography, Hyflo Super Gel®=filtration aid (Fluka), ISN=ion spray negative (mode), ISP=ion spray positive (mode), NMP=N-methylpyrrolidon, NMR=nuclear magnetic resonance, MPLC=medium pressure liquid chromatography, MS=mass spectrum, P=protecting group, R=any group, rt=room temperature, THF=tetrahydrofuran, X=halogen, Y=any group including heteroatoms and halides.

Example 1 (2-Chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine Step 1 [1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester

A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (10.0 g, 50.0 mmol, 1.0 equiv), 3-ethoxy-4-methoxy-benzaldehyde (10.8 g, 60.0 mmol, 1.2 equiv; commercially available) and acetic acid (11.4 mL, 12.01 g, 200.0 mmol, 4.0 equiv) in ethanol (40 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (6.27 g, 100.0 mmol, 2.0 equiv), dissolved in ethanol (20 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 5 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with ethyl acetate to yield 9.71 g (53%) of the title compound as a white solid. MS (ISP): 365.3 [M+H]⁺.

Step 2 1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (Intermediate A1)

A solution of [1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (9.71 g, 26.64 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (200 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄ and concentrated by evaporation under reduced pressure yielding 4.69 g (89%) of a white solid. The crude material was directly used in the following reaction step. MS (ESI): 265.0 [M+H]⁺.

Step 3 (Method A)

To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) under Ar was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,4-dichloro-pyrimidine (18.6 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 1 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.9 mg (23%) of the title compound. MS (ISP): 377.2 [M+H]⁺.

Example 2 2-Chloro-N-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-N′-isopropyl-pyrimidine-4,6-diamine Step 1 (2,6-Dichloro-pyrimidin-4-yl)-isopropyl-amine [CAS RN 30297-43-9]

The title compound was prepared according to DE 2006 145 A1 (Sandoz A G).

Step 2 (Method B)

To a solution of 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.2 equiv; intermediate A1) in dry DMF (1.5 mL) was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt under Ar. After 2 h, (2,6-dichloro-pyrimidin-4-yl)-isopropyl-amine (25.8 mg, 0.125 mmol, 1.0 equiv) was added and the mixture heated to 120° C. for 48 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 7.1 mg (13%) of the title compound. MS (ISP): 434.3 [M+H]⁺.

Example 3 (2-Chloro-5-methyl-pyrimidin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine Method C:

A solution of 2,4-dichloro-5-methyl-pyrimidine (16.3 mg, 0.10 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (39.7 mg, 0.15 mmol, 1.5 equiv; intermediate A1) in ethylene glycol (2 mL) was heated by microwave irradiation to 200° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 4.0 mg (7%) of the title compound. MS (ESI): 391.4 [M+H]⁺.

Example 4 N-{2-Chloro-6-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamino]-pyrimidin-4-yl}-acetamide Step 1 N-(2,6-Dichloro-pyrimidin-4-yl)-acetamide (Intermediate B1) [CAS RN 89581-87-3]

The title compound was prepared according to WO 05/026 149 A1 (AstraZeneca UK Limited).

Step 2 (Method D)

A solution of N-(2,6-dichloro-pyrimidin-4-yl)-acetamide (30.9 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 15 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.6 mg (3%) of the title compound. MS (ISP): 434.4 [M+H]⁺.

Example 5 N⁴-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-6-methyl-pyrimidine-2,4-diamine Method E

A solution of 4-chloro-6-methyl-pyrimidin-2-ylamine (21.5 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 180° C. for 40 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 6.1 mg (11%) of the title compound. MS (ISP): 372.3 [M+H]⁺.

Example 6 (2,7-Dichloro-quinazolin-4-yl)-[1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-amine Step 1 2,4,7-Trichloro-quinazoline [CAS RN 6625-94-1]

The title compound was prepared according to WO 05/049 033 A1 (Astra Zeneca UK Limited).

Step 2 (Method F)

A solution of 2,4,7-trichloro-quinazoline (35.0 mg, 0.15 mmol, 1.0 equiv) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (2 mL) was heated by microwave irradiation to 200° C. for 30 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.8 mg (3%) of the title compound. MS (ISP): 461.3 [M+H]⁺.

Example 7 [1-(3-Ethoxy-4-methoxy-benzyl)-piperidin-4-yl]-(2-phenyl-quinazolin-4-yl)-amine Method G:

A solution of 4-chloro-2-phenyl-quinazoline (36.1 mg, 0.15 mmol, 1.0 equiv; commercially available) and 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (47.6 mg, 0.18 mmol, 1.2 equiv; intermediate A1) in DMAc (1.5 mL) was heated by microwave irradiation to 180° C. for 10 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 1.6 mg (3%) of the title compound. MS (ISP): 469.4 [M+H]⁺.

The pyrimidine and quinazoline intermediates B2 and B3 were prepared following literature precedents.

Synthesis of Pyrimidine and Quinazoline Intermediates B2 and B3 to be used in Table 1 Intermediate B2 4-Azetidin-1-yl-2,6-dichloro-pyrimidine [CAS RN 202467-33-2]

The title compound was prepared according to EP 0815 861 A1 (F. Hoffmann-La Roche A G).

Intermediate B3 2,4,7-Trichloro-6-fluoro-quinazoline [CAS RN 174866-16-6]

The title compound was prepared according to WO 95/32 205 A1 (F. Hoffmann-La Roche A G).

Examples 8 to 16

According to the procedure described for the synthesis of example 1/step 3 (Method A), example 2/step 2 (Method B), example 3 (Method C) and example 4/step 2 (Method D) further pyrimidine and quinazoline derivatives have been synthesized from 1-(3-ethoxy-4-methoxy-benzyl)-piperidin-4-ylamine (intermediate A1) and the respective pyrimidine and quinazoline intermediate as indicated in Table 1. The results are compiled in Table 1 and comprise example 8 to example 16.

TABLE 1 ISP [M + H]⁺ No MW Compound Name Preparation Starting Materials found 8 394.88 (2-chloro-5-fluoro- Method A 1-(3-ethoxy-4-methoxy- 395.3 pyrimidin-4-yl)-[1-(3- benzyl)-piperidin-4- ethoxy-4-methoxy- ylamine (intermediate A1) benzyl)-piperidin-4- and 2,4-dichloro-5-fluoro- yl]-amine pyrimidine (commercially available) 9 411.33 (2,6-dichloro- Method A 1-(3-ethoxy-4-methoxy- 411.1 pyrimidin-4-yl)-[1-(3- benzyl)-piperidin-4- ethoxy-4-methoxy- ylamine (intermediate A1) benzyl)-piperidin-4- and 2,4,6-trichloro- yl]-amine pyrimidine (commercially available) 10 445.78 [1-(3-ethoxy-4- Method A 1-(3-ethoxy-4-methoxy- 447.0 methoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-yl]-(2,5,6- ylamine (intermediate A1) trichloro-pyrimidin- and 2,4,5,6-tetrachloro- 4-yl)-amine pyrimidine (commercially available) 11 391.90 6-chloro-N⁴-[1-(3- Method A 1-(3-ethoxy-4-methoxy- 392.2 ethoxy-4-methoxy- benzyl)-piperidin-4- benzyl)-piperidin-4- ylamine (intermediate A1) yl]-pyrimidine-2,4- and 4,6-dichloro- diamine pyrimidin-2-ylamine (commercially available) 12 391.90 6-chloro-N⁴-[1-(3- Method A 1-(3-ethoxy-4-methoxy- 392.2 ethoxy-4-methoxy- benzyl)-piperidin-4- benzyl)-piperidin-4- ylamine (intermediate A1) yl]-pyrimidine-4,5- and 4,6-dichloro- diamine pyrimidin-5-ylamine (commercially available) 13 431.97 (6-azetidin-1-yl-2- Method B 1-(3-ethoxy-4-methoxy- 432.4 chloro-pyrimidin-4- benzyl)-piperidin-4- yl)-[1-(3-ethoxy-4- ylamine (intermediate A1) methoxy-benzyl)- and 4-azetidin-1-yl-2,6- piperidin-4-yl]-amine dichloro-pyrimidine (intermediate B2) 14 426.95 (7-chloro-quinazolin- Method A 1-(3-ethoxy-4-methoxy- 427.3 4-yl)-[1-(3-ethoxy-4- benzyl)-piperidin-4- methoxy-benzyl)- ylamine (intermediate A1) piperidin-4-yl]-amine and 4,7-dichloro- quinazoline (commercially available) 15 479.38 (2,7-dichloro-6- Method C 1-(3-ethoxy-4-methoxy- 479.4 fluoro-quinazolin-4- benzyl)-piperidin-4- yl)-[1-(3-ethoxy-4- ylamine (intermediate A1) methoxy-benzyl)- and 2,4,7-trichloro-6- piperidin-4-yl]-amine fluoro-quinazoline (intermediate B3) 16 487.00 (2-chloro-6,7- Method D 1-(3-ethoxy-4-methoxy- 487.3 dimethoxy- benzyl)-piperidin-4- quinazolin-4-yl)-[1- ylamine (intermediate A1) (3-ethoxy-4-methoxy- and 2,4-dichloro-6,7- benzyl)-piperidin-4- dimethoxy-quinazoline yl]-amine (commercially available)

Example 17 [1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methyl-pyrimidin-4-yl)-amine Step 1 [1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester

A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (5.0 g, 25.0 mmol, 1.0 equiv), 4-chloro-3-ethoxy-benzaldehyde (5.54 g, 30.0 mmol, 1.2 equiv; intermediate D2, vide infra) and acetic acid (5.7 mL, 6.01 g, 100.0 mmol, 4.0 equiv) in ethanol (25 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (3.14 g, 50.0 mmol, 2.0 equiv), dissolved in ethanol (10 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.91 g (42%) of the title compound. MS (ISP): 369.0 [M+H]⁺.

Step 2 1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (Intermediate A2)

A solution of [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (0.78 g, 2.12 mmol) in ethanol (10 mL) and 4 M HCl (15 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (50 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO₄ and concentrated by evaporation under reduced pressure yielding 0.32 g (57%) of a white solid. The crude material was directly used in the following reaction step. MS (ISP): 269.0 [M+H]⁺.

Step 3 (Method B)

To a solution of 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (40.3 mg, 0.15 mmol, 1.2 equiv; intermediate A2) in dry DMF (1.5 mL) was added sodium hydride (6.6 mg, 0.15 mmol, 1.2 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt under Ar. After 2 h, 2,4-dichloro-5-methyl-pyrimidine (20.4 mg, 0.125 mmol, 1.0 equiv; commercially available) was added and the mixture heated to 120° C. for 48 h. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 3.7 mg (8%) of the title compound. MS (ISP): 395.2 [M+H]⁺.

The pyrimidine intermediate B4 was prepared following literature precedents.

Synthesis of Pyrimidine Intermediate B4 to be used in Table 2 Intermediate B4 2,4-Dichloro-5-(2-ethyl-4,5-dimethoxy-benzyl)-pyrimidine [CAS RN 6981-20-0]

The title compound was prepared according to NL 6514 743 A (F. Hoffmann-La Roche A G).

Examples 18 to 24

According to the procedure described for the synthesis of example 1/step 3 (Method A) and example 2/step 2 (Method B) further pyrimidine, quinazoline and purine derivatives have been synthesized from 1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-ylamine (intermediate A2) and the respective pyrimidine, quinazoline and purine intermediate as indicated in Table 2. The results are compiled in Table 2 and comprise example 18 to example 24.

TABLE 2 ISP [M + H]⁺ No MW Compound Name Preparation Starting Materials found 18 381.31 [1-(4-chloro-3- Method B 1-(4-chloro-3-ethoxy- 381.3 ethoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-yl]-(2- ylamine (intermediate A2) chloro-pyrimidin-4- and 2,4-dichloro- yl)-amine pyrimidine (commercially available) 19 399.30 [1-(4-chloro-3- Method B 1-(4-chloro-3-ethoxy- 399.2 ethoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-yl]-(2- ylamine (intermediate A2) chloro-5-fluoro- and 2,4-dichloro-5-fluoro- pyrimidin-4-yl)- pyrimidine (commercially amine available) 20 396.32 6-chloro-N⁴-[1-(4- Method B 1-(4-chloro-3-ethoxy- 396.3 chloro-3-ethoxy- benzyl)-piperidin-4- benzyl)-piperidin-4- ylamine (intermediate A2) yl]-pyrimidine-4,5- and 4,6-dichloro- diamine pyrimidin-5-ylamine (commercially available) 21 438.36 N-{2-chloro-6-[1-(4- Method B 1-(4-chloro-3-ethoxy- 438.3 chloro-3-ethoxy- benzyl)-piperidin-4- benzyl)-piperidin-4- ylamine (intermediate A2) ylamino]-pyrimidin- and N-(2,6-dichloro- 4-yl}-acetamide pyrimidin-4-yl)-acetamide (intermediate B1) 22 559.54 [1-(4-chloro-3- Method B 1-(4-chloro-3-ethoxy- 559.3 ethoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-yl]-[2- ylamine (intermediate A2) chloro-5-(2-ethyl-4,5- and 2,4-dichloro-5-(2- dimethoxy-benzyl)- ethyl-4,5-dimethoxy- pyrimidin-4-yl]- benzyl)-pyrimidine amine (intermediate B4) 23 431.37 [1-(4-chloro-3- Method A 1-(4-chloro-3-ethoxy- 431.3 ethoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-yl]-(7- ylamine (intermediate A2) chloro-quinazolin-4- and 4,7-dichloro- yl)-amine quinazoline (commercially available) 24 401.90 N⁶-[1-(4-chloro-3- Method B 1-(4-chloro-3-ethoxy- 402.4 ethoxy-benzyl)- benzyl)-piperidin-4- piperidin-4-yl]-9H- ylamine (intermediate A2) purine-2,6-diamine and 6-chloro-9H-purin-2- ylamine (commercially available)

Example 25 6-Chloro-N⁴-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-pyrimidine-4,5-diamine Step 1 [1-(3,5-Diisopropoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester

A mixture of piperidin-4-yl-carbamic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.0 equiv), 3,5-diisopropoxy-benzaldehyde (5.33 g, 24.0 mmol, 1.2 equiv; intermediate D7, vide infra) and acetic acid (4.6 mL, 4.80 g, 80.0 mmol, 4.0 equiv) in ethanol (16 mL) was heated by microwave irradiation to 100° C. for 5 min. Sodium cyanoborohydride (2.51 g, 40.0 mmol, 2.0 equiv), dissolved in ethanol (8 mL), was added and the reaction mixture heated by microwave irradiation to 100° C. for an additional time period of 10 min. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄, concentrated by evaporation under reduced pressure and the crude material purified on a Isolute flash NH2 chromatography column using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.23 g (40%) of the title compound. MS (ISP): 407.4 [M+H]⁺.

Step 2 1-(3,5-Diisopropoxy-benzyl)-piperidin-4-ylamine (Intermediate A3)

A solution of [1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-carbamic acid tert-butyl ester (3.23 g, 7.95 mmol) in 4 M HCl (100 mL) was stirred at rt for 2 h. The hydrochloric acid was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄ and concentrated by evaporation under reduced pressure yielding 0.78 g (32%) of a colorless oil.

The crude material was directly used in the following reaction step. MS (ISP): 307.5 [M+H]⁺.

Step 3 (Method H)

A solution of 4,6-dichloro-pyrimidin-5-ylamine (19.7 mg, 0.12 mmol, 1.0 equiv; commercially available) and 1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamine (46.0 mg, 0.15 mmol, 1.25 equiv; intermediate A3) in N-ethyl diisopropylamine (1.0 mL) and acetonitril (1.0 mL) was heated by microwave irradiation to 160° C. for 20 min. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 10.6 mg (20%) of the title compound. MS (ISP): 434.3 [M+H]⁺.

Synthesis of Pyrimidine Intermediates B5 to B11 to be used in Table 3 Intermediate B5 4,6-Dichloro-5-phenoxy-pyrimidine [CAS RN 90876-79-2]

The title compound was prepared according to U.S. Pat. No. 5,292,740 (F. Hoffmann-La Roche A G).

Intermediate B6 4,6-Dichloro-5-o-tolyloxy-pyrimidine [CAS RN 150743-55-8]

The title compound was prepared according to U.S. Pat. No. 5,292,740 (F. Hoffmann-La Roche A G).

Intermediate B7 4,6-Dichloro-5-(2-methoxy-phenoxy)-pyrimidine [CAS RN 150727-23-4]

The title compound was prepared according to U.S. Pat. No. 5,292,740 (F. Hoffmann-La Roche A G).

Intermediate B8 4,6-Dichloro-5-(2-ethoxy-phenoxy)-pyrimidine [CAS RN 150727-94-9]

The title compound was prepared according to U.S. Pat. No. 5,292,740 (F. Hoffmann-La Roche A G).

Intermediate B9 4,6-Dichloro-5-(4-methoxy-phenoxy)-pyrimidine [CAS RN 150727-32-5]

The title compound was prepared according to U.S. Pat. No. 5,292,740 (F. Hoffmann-La Roche A G).

Intermediate B10 4,6-Dichloro-5-(2-methoxy-benzyl)-pyrimidine [CAS RN 146532-80-1]

The title compound was prepared according to EP 510 526 B1 (F. Hoffmann-La Roche A G).

Intermediate B11 4,6-Dichloro-5-(2-trifluoromethyl-benzyl)-pyrimidine [CAS RN 146532-58-3]

The title compound was prepared according to EP 510 526 B1 (F. Hoffmann-La Roche A G).

Examples 26 to 33

According to the procedure described for the synthesis of example 25/step 3 (Method H) further pyrimidine derivatives have been synthesized from 1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamine (intermediate A3) and the respective pyrimidine intermediate as indicated in Table 3. The results are compiled in Table 3 and comprise example 26 to example 33.

TABLE 3 ISP [M + H]⁺ No MW Compound Name Preparation Starting Materials found 26 511.07 (6-chloro-5-phenoxy- Method H 1-(3,5-diisopropoxy- 511.4 pyrimidin-4-yl)-[1- benzyl)-piperidin-4- (3,5-diisopropoxy- ylamine (intermediate A3) benzyl)-piperidin-4- and 4,6-dichloro-5- yl]-amine phenoxy-pyrimidine (intermediate B5) 27 525.09 (6-chloro-5-o- Method H 1-(3,5-diisopropoxy- 525.2 tolyloxy-pyrimidin-4- benzyl)-piperidin-4- yl)-[1-(3,5- ylamine (intermediate A3) diisopropoxy-benzyl)- and 4,6-dichloro-5-o- piperidin-4-yl]-amine tolyloxy-pyrimidine (intermediate B6) 28 541.09 [6-chloro-5-(2- Method H 1-(3,5-diisopropoxy- 541.3 methoxy-phenoxy)- benzyl)-piperidin-4- pyrimidin-4-yl]-[1- ylamine (intermediate A3) (3,5-diisopropoxy- and 4,6-dichloro-5-(2- benzyl)-piperidin-4- methoxy-phenoxy)- yl]-amine pyrimidine_(intermediate B7) 29 555.12 [6-chloro-5-(2- Method H 1-(3,5-diisopropoxy- 555.3 ethoxy-phenoxy)- benzyl)-piperidin-4- pyrimidin-4-yl]-[1- ylamine (intermediate A3) (3,5-diisopropoxy- and 4,6-dichloro-5-(2- benzyl)-piperidin-4- ethoxy-phenoxy)- yl]-amine pyrimidine_(intermediate B8) 30 541.09 [6-chloro-5-(4- Method H 1-(3,5-diisopropoxy- 541.3 methoxy-phenoxy)- benzyl)-piperidin-4- pyrimidin-4-yl]-[1- ylamine (intermediate A3) (3,5-diisopropoxy- and 4,6-dichloro-5-(4- benzyl)-piperidin-4- methoxy-phenoxy)- yl]-amine pyrimidine (intermediate B9) 31 539.12 [6-chloro-5-(2- Method H 1-(3,5-diisopropoxy- 539.5 methoxy-benzyl)- benzyl)-piperidin-4- pyrimidin-4-yl]-[1- ylamine (intermediate A3) (3,5-diisopropoxy- and 4,6-dichloro-5-(2- benzyl)-piperidin-4- methoxy-benzyl)- yl]-amine pyrimidine (intermediate B10) 32 577.09 [6-chloro-5-(2- Method H 1-(3,5-diisopropoxy- 577.4 trifluoromethyl- benzyl)-piperidin-4- benzyl)-pyrimidin-4- ylamine (intermediate A3) yl]-[1-(3,5- and 4,6-dichloro-5-(2- diisopropoxy-benzyl)- trifluoromethyl-benzyl)- piperidin-4-yl]-amine pyrimidine (intermediate B11) 33 423.56 [1-(3,5-diisopropoxy- Method H 1-(3,5-diisopropoxy- 424.3 benzyl)-piperidin-4- benzyl)-piperidin-4- yl]-(7H-pyrrolo[2,3- ylamine (intermediate A3) d]pyrimidin-4-yl)- and 4-chloro-7H- amine pyrrolo[2,3-d]pyrimidine (commercially available)

Example 34 (2-Chloro-pyrimidin-4-yl)-[1-(3-ethoxy-4-methyl-benzyl)-piperidin-4-yl]-amine Step 1 4-(2-Chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A mixture of 2,4-dichloro-pyrimidine (4.0 g, 26.85 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (6.45 g, 32.22 mmol, 1.2 equiv) in anhydrous DMF (100 mL) was stirred at rt for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.2 g (38%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ1.35-1.45 (m, 2H), 1.47 (s, 9H), 1.99-2.03 (m, 2H), 2.91-2.97 (m, 2H), 3.81-3.90 (m, 1H), 4.04-4.07 (br d, 2H), 5.33 (d, J=8.0 Hz, 1H), 6.25 (d, J=4.0 Hz, 1H), 7.98 (d, J=4.0 Hz, 1H). ¹³C NMR (75 MHz, DMSO): δ 28.05, 30.94, 42.04, 46.69, 78.64, 105.13, 153.86, 155.57, 159.81, 162.72. MS (ISP): 313.1 [M+H]⁺.

Step 2 (2-Chloro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (Intermediate C1)

A solution of 4-(2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.2 g, 10.23 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (70 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 213.3 [M+H]⁺.

Step 3

To a solution of (2-chloro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (42.9 mg, 0.15 mmol, 1.0 equiv; intermediate C1) in ethanol (2 mL), acetic acid (72.1 mg, 1.2 mmol, 8.0 equiv) and N-ethyl diisopropylamine (77.6 mg, 0.6 mmol, 4.0 equiv) was added 3-ethoxy-4-methyl-benzaldehyde (29.6 mg, 0.18 mmol, 1.2 equiv; intermediate D10, vide infra) and the mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.4 mg (4%) of the title compound. MS (ISP): 361.3 [M+H]⁺.

The pyrimidine, quinazoline and purine piperidine intermediates C2 to C14 were prepared following literature precedents or as described below.

Synthesis of Pyrimidine, Quinazoline and Purine Piperidine Intermediates C2 to C14 to be used in Table 4 Intermediate C2 (2-Chloro-6-methyl-pyrimidin-4-yl)-piperidin-4-yl)-amine dihydrochloride

Step 1 4-(2-Chloro-6-methyl-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 2,4-dichloro-6-methyl-pyrimidine (1.25 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.15 g (46%) of the title compound. ¹H NMR (400 MHz, DMSO): δ 1.24-1.31 (m, 2H), 1.40 (s, 9H), 1.80-1.83 (br d, 2H), 2.18 (s, 3H), 2.90 (br s, 2H), 3.87 (br s, 2H), 3.96 (br s, 1H), 6.23 (br s, 1H), 7.68 (d, J=8.0 Hz, 1H). MS (ISP): 327.4 [M+H]⁺.

Step 2

A solution of 4-(2-chloro-6-methyl-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.15 g, 3.52 mmol) in 4 M HCl in dioxane (70 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 225.3 [M+H]⁺.

Intermediate C3 (2,6-Dichloro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride

Step 1 4-(2,6-Dichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.0 g, 20.0 mmol, 1.3 equiv) in dry DMF (100 mL) under Ar was added sodium hydride (1.01 g, 23.1 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 2,4,6-trichloro-pyrimidine (2.82 g, 15.4 mmol, 1.0 equiv; commercially available) was added and the mixture stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude reaction product extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄, concentrated by evaporation under reduced pressure and the crude material purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate to provide 3.1 g (57%) of the title compound. ¹H NMR (400 MHz, DMSO): δ 1.24-1.33 (m, 2H), 1.40 (s, 9H), 1.78-1.85 (m, 2H), 2.86-2.96 (m, 2H), 3.49-3.97 (m, 3H), 6.47 (s, 1H). MS (ISP): 347.3 [M+H]⁺.

Step 2

A solution of 4-(2,6-dichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.1 g, 8.93 mmol) in ethanol (40 mL) and 4 M HCl in dioxane (70 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 247.3 [M+H]⁺.

Intermediate C4 4-Methoxy-6-(piperidin-4-ylamino)-pyrimidin-2-ol dihydrochloride

Step 1 4-(2,6-Dimethoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 4-chloro-2,6-dimethoxy-pyrimidine (1.92 g, 11.0 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.64 g, 13.20 mmol, 1.2 equiv) and N-ethyl diisopropylamine (2.24 mL, 1.71 g, 13.20 mmol, 1.2 equiv) in acetonitrile (8 mL) and DMAc (2 mL) was heated by microwave irradiation to 160° C. for 1 h and then to 180° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.22 g (33%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.39-1.48 (m, 2H), 1.46 (s, 9H), 1.97-2.00 (m, 2H), 2.85-2.96 (m, 2H), 3.86 (s, 3H), 3.89 (s, 3H), 3.96-4.02 (m, 3H), 5.52 (d, J=7.9 Hz, 1H). ¹³C NMR (75 MHz, CDCl₃): δ28.16, 31.48, 42.39, 47.95, 53.12, 53.76, 79.24, 100.51, 154.40, 164.60, 164.99, 171.52. MS (ISP): 339.4 [M+H]⁺.

Step 2

A solution of 4-(2,6-dimethoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.71 g, 2.10 mmol) in ethanol (10 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 48 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 225.4 [M+H]⁺.

Intermediate C5 2-Chloro-6-(piperidin-4-ylamino)-pyrimidine-4-carboxylic acid methyl ester dihydrochloride

Step 1 6-(1-tert-Butoxycarbonyl-piperidin-4-ylamino)-2-chloro-pyrimidine-4-carboxylic acid methyl ester

A mixture of 2,6-dichloro-pyrimidine-4-carboxylic acid methyl ester (3.98 g, 19.19 mmol, 1.0 equiv; commercially available) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (5.0 g, 24.94 mmol, 1.3 equiv) in anhydrous DMF (100 mL) was heated to 60° C. for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture extracted from a 1 M NaOH (100 mL) solution with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO₄ and the product purified with silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 3.46 g (49%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.42-1.51 (m, 2H), 1.47 (s, 9H), 2.00-2.05 (m, 2H), 2.90-3.01 (m, 2H), 3.92 (s, 3H), 4.05-4.10 (m, 2H), 4.19 (br s, 1H), 7.10 (s, 1H), 7.17 (br s, 1H). ¹³C NMR (75 MHz, CDCl₃): δ28.30, 31.23, 42.41, 48.00, 52.88, 79.61, 106.38, 153.58, 154.61, 161.21, 163.75, 164.23. MS (ISP): 371.1 [M+H]⁺.

Step 2

A solution of 6-(1-tert-butoxycarbonyl-piperidin-4-ylamino)-2-chloro-pyrimidine-4-carboxylic acid methyl ester (3.46 g, 9.34 mmol) in ethanol (50 mL) and 4 M HCl in dioxane (75 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 271.1 [M+H]⁺.

Intermediate C6 N-[2-Chloro-6-(piperidin-4-ylamino)-pyrimidin-4-yl]-acetamide dihydrochloride

Step 1 4-(6-Acetylamino-2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A mixture of N-(2,6-dichloro-pyrimidin-4-yl)-acetamide (0.7 g, 3.40 mmol, 1.0 equiv; intermediate B1) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.82 g, 4.08 mmol, 1.2 equiv) in anhydrous DMF (6 mL) was heated by microwave irradiation to 130° C. for 4 h. Removal of the solvent under reduced pressure and purification with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (3:1→1:1) provided 0.1 g (8%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.33-1.45 (m, 2H), 1.47 (s, 9H), 1.97-2.08 (m, 2H), 2.18 (s, 3H), 2.90-2.99 (m, 2H), 4.01-4.08 (m, 3H), 5.19 (br s, 1H), 7.13 (s, 1H), 8.04 (br s, 1H). MS (ISP): 370.1 [M+H]⁺.

Step 2

A solution of 4-(6-acetylamino-2-chloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.1 g, 0.27 mmol) in ethanol (2 mL) and 4 M HCl in dioxane (2 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 270.0 [M+H]⁺.

Intermediate C7 (2-Chloro-5-fluoro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride

Step 1 4-(2-Chloro-5-fluoro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 2,4-dichloro-5-fluoro-pyrimidine (1.28 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 2.23 g (88%) of the title compound. ¹H NMR (400 MHz, DMSO): δ 1.38-1.48 (m, 2H), 1.41 (s, 9H), 1.78-1.82 (m, 2H), 2.84 (br s, 2H), 3.93-3.96 (m, 2H), 4.00-4.08 (m, 1H), 8.02 (d, J=6.0 Hz, 1H), 8.09 (d, J=4.0 Hz, 1H). ¹³C NMR (100 MHz, DMSO): δ 28.06, 30.75, 43.33, 47.34, 78.66, 139.86 (d, J=20.3 Hz), 145.03 (d, J=255.7 Hz), 152.63 (d, J=13.4 Hz), 153.49 (d, J=2.7 Hz), 153.83. MS (ISP): 331.3 [M+H]⁺.

Step 2

A solution of 4-(2-chloro-5-fluoro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 6.05 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 231.1 [M+H]⁺.

Intermediate C8 (2-Chloro-5-methoxy-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride

Step 1 4-(2-Chloro-5-methoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 2,4-dichloro-5-methoxy-pyrimidine (0.80 g, 4.47 mmol, 1.0 equiv; commercially available from Specs Research Laboratory, The Netherlands), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.34 g, 6.70 mmol, 1.5 equiv) and triethylamine (0.93 mL, 0.68 g, 6.70 mmol, 1.5 equiv) in acetonitrile (9 mL) and DMAc (2 mL) was heated by microwave irradiation to 120° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 1.43 g (93%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ1.28-1.49 (m, 2H), 1.40 (s, 9H), 1.93-1.98 (m, 2H), 2.85-2.92 (m, 2H), 3.80 (s, 3H), 3.97-4.02 (m, 2H), 4.06-4.12 (m, 1H), 5.22 (d, J=8.0 Hz, 1H), 7.46 (s, 1H). MS (ISP): 343.3 [M+H]⁺.

Step 2

A solution of 4-(2-chloro-5-methoxy-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.43 g, 4.17 mmol) in dichloromethane (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 243.3 [M+H]⁺.

Intermediate C9 (2-Chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride

Step 1 2,4-Dichloro-6,7-dihydro-5H-cyclopentapyrimidine [CAS RN 5466-43-3]

The title compound was prepared as described in Y.-Z. Kim, J.-C. Lim, J.-H. Yeo, C.-S. Bang, W.-S. Kim, S.-S. Kim, Y.-M. Woo, D.-H. Yang, H. Oh and K. Nahm J. Med. Chem. 1994, 37, 3828-3833.

Step 2 4-(2-Chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A mixture of 2,4-dichloro-6,7-dihydro-5H-cyclopentapyrimidine (2.71 g, 14.34 mmol, 1.0 equiv) and 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.45 g, 17.20 mmol, 1.2 equiv) in anhydrous DMF (40 mL) was heated to 60° C. for 18 h. The organic phase was concentrated under reduced pressure and the crude reaction mixture extracted from a solution of 1 M NaOH (100 mL) with ethyl acetate (3×50 mL). The combined organic phases were dried over MgSO₄ and the product purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (14:3→1:1) providing 2.34 g (47%) of the title compound. ¹H NMR (300 MHz, DMSO): δ 1.32-1.43 (m, 2H), 1.39 (s, 9H), 1.79-1.82 (m, 2H), 2.0 (quint, J=7.5 Hz, 2H), 2.61 (t, J=7.5 Hz, 2H), 2.70 (t, J=7.5 Hz, 2H), 2.80-2.88 (m, 2H), 3.93-3.98 (m, 2H), 4.04-4.13 (m, 1H), 7.07 (d, J=8.0 Hz, 1H). ¹³C NMR (75 MHz, DMSO): δ 21.12, 26.42, 28.04, 31.17, 33.19, 42.55, 47.12, 78.53, 114.87, 153.84, 157.95, 159.02, 172.18. MS (ISP): 353.1 [M+H]⁺.

Step 3

A solution of 4-(2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.34 g, 6.63 mmol) in MeOH (10 mL) and 4 M HCl in dioxane (20 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 253.1 [M+H]⁺.

Intermediate C10 [2,4-Dichloro-6-(piperidin-4-ylamino)-pyrimidin-5-yl]-acetic acid ethyl ester dihydrochloride

Step 1 4-(2,6-Dichloro-5-ethoxycarbonylmethyl-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of (2,4,6-trichloro-pyrimidin-5-yl)-acetic acid ethyl ester (1.00 g, 3.71 mmol, 1.0 equiv; commercially available from Tyger Scientific Inc, USA), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (1.26 g, 6.31 mmol, 1.7 equiv) and triethylamine (0.77 mL, 0.56 g, 5.57 mmol, 1.5 equiv) in acetonitrile (9 mL) and DMAc (2 mL) was heated by microwave irradiation to 120° C. for 30 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.87 g (54%) of the title compound. ¹H NMR (400 MHz, DMSO): δ 1.19 (t, J=8.0 Hz, 3H), 1.35-1.44 (m, 2H), 1.40 (s, 9H), 1.76-1.79 (m, 2H), 2.84 (br s, 2H), 3.73 (s, 2H), 3.93-3.96 (m, 2H), 4.11 (q, J=8.0 Hz, 2H), 4.08-4.13 (m, 1H), 7.52 (d, J=8.0 Hz, 1H). MS (ISP): 433.3 [M+H]⁺.

Step 2

A solution of 4-(2,6-dichloro-5-ethoxycarbonylmethyl-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 2.01 mmol) in dichloromethane (10 mL) and 4 M HCl in dioxane (40 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 333.1 [M+H]⁺.

Intermediate C11 Piperidin-4-yl-(2,5,6-trichloro-pyrimidin-4-yl)-amine dihydrochloride

Step 1 4-(2,5,6-Trichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 2,4,5,6-tetrachloro-pyrimidine (1.67 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 0.85 g (29%) of the title compound. ¹H NMR (400 MHz, DMSO): δ 1.41 (s, 9H), 1.49-1.60 (m, 2H), 1.73-1.77 (m, 2H), 2.81 (br s, 2H), 3.95-3.98 (m, 2H), 4.09-4.16 (m, 1H), 7.88 (d, J=8.0 Hz, 1H). ¹³C NMR (100 MHz, DMSO): δ 28.07, 30.45, 43.33, 48.90, 78.65, 109.37, 153.80, 154.62, 155.66, 158.74. MS (ISP): 383.0 [M+H]⁺.

Step 2

A solution of 4-(2,5,6-trichloro-pyrimidin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.85 g, 2.23 mmol) in 4 M HCl in dioxane (100 mL) was stirred at rt for 2 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 283.4 [M+H]⁺.

Intermediate C12 (7-Chloro-quinazolin-4-yl)-piperidin-4-yl-amine dihydrochloride

Step 1 4-(7-Chloro-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 4-amino-piperidine-1-carboxylic acid tert-butyl ester (3.62 g, 18.1 mmol, 1.2 equiv) in dry DMF (20 mL) under Ar was added sodium hydride (0.99 g, 22.7 mmol, 1.5 equiv; 55% free-flowing powder moistened with oil) and the reaction mixture stirred at rt. After 2 h, 4,7-dichloro-quinazoline (3.0 g, 15.1 mmol, 1.0 equiv; commercially available) was added and the mixture heated by microwave irradiation to 140° C. for 30 min. Removal of the solvent under reduced pressure and purification with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (10:1→1:1) afforded 4-(7-chloro-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.33 g, 79%). ¹H NMR (300 MHz, CDCl₃): δ1.42-1.53 (m, 2H), 1.48 (s, 9H), 2.16-2.18 (m, 2H), 2.92-2.98 (m, 2H), 4.17-4.20 (m, 2H), 4.39-4.49 (m, 1H), 5.79 (d, J=8.0 Hz, 1H), 7.40 (dd, J=8.8 Hz, J=2.1 Hz, 1H), 7.71 (d, J=8.8 Hz, 1H), 7.82 (d, J=2.1 Hz, 1H), 8.63 (s, 1H). ¹³C NMR (75 MHz, CDCl₃): δ28.50, 32.05, 42.89, 48.38, 79.85, 113.29, 122.11, 126.75, 127.89, 138.70, 150.65, 154.78, 156.37, 158.58. MS (ISP): 363.5 [M+H]⁺.

Step 2

A solution of 4-(7-chloro-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (4.33 g, 11.9 mmol) in dioxane (35 mL) and conc. HCl (10 mL) was stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ESP): 263.0 [M+H]⁺.

Intermediate C13 (2-Chloro-6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl-amine dihydrochloride

Step 1 4-(2-Chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

To a solution of 2,4-dichloro-6,7-dimethoxyquinazoline (5.12 g, 19.8 mmol, 1.0 equiv) in THF (50 mL) was added 4-amino-piperidine-1-carboxylic acid tert-butyl ester (4.34 g, 21.7 mmol, 1.1 equiv) and 1,8-diazabicyclo [5.4.0]undec-7-ene (3.31 g, 3.25 mL, 21.7 mmol, 1.1 equiv) and the reaction mixture stirred at rt for 16 h. Additional 4-amino-piperidine-1-carboxylic acid tert-butyl ester (0.87 g, 4.3 mmol, 0.2 equiv) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.66 g, 0.65 mL, 4.3 mmol, 0.2 equiv) were added and the mixture was stirred for 2 h. The solvent was evaporated under reduced pressure and the mixture dissolved in dichloromethane (100 mL). The solution was washed with water (2×20 mL) and a sat. solution of NaCl (20 mL), the aqueous layers were combined and extracted with dichloromethane (20 mL). The combined organic layers were dried over MgSO₄ and evaporated under reduced pressure to give an amber solid. The solid was crystallized from MeOH (500 mL) to afford 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (2.67 g, 22%) as a white solid. The mother liquors were evaporated and purified with column chromatography on silica eluting with a gradient of heptane/ethyl acetate (1:1)→ethyl acetate and the fractions combined to afford additional 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (1.0 g, 12%). ¹H NMR (250 MHz, CDCl₃): δ1.49-1.51 (m, 2H), 1.61 (s, 9H), 2.30-2.48 (m, 2H), 2.89-3.10 (m, 2H), 4.04 (s, 3H), 4.09 (s, 3H), 4.29-4.48 (m, 2H), 4.75-4.50 (m, 1H), 5.61 (d, J=8.0 Hz, 1H), 6.87 (s, 1H), 7.18 (s, 1H). MS (ESP): 423.5 [M+H]⁺.

Step 2

A solution of 4-(2-chloro-6,7-dimethoxy-quinazolin-4-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (3.65 g, 8.6 mmol) in dioxane (35 mL) and conc. HCl (5 mL) was stirred at rt for 18 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ESP): 323.3 [M+H]⁺.

Intermediate C14 Piperidin-4-yl-(9H-purin-6-yl)-amine dihydrochloride

Step 1 4-(9H-Purin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester

A solution of 6-chloro-9H-purine (1.19 g, 7.68 mmol, 1.0 equiv; commercially available), 4-amino-piperidine-1-carboxylic acid tert-butyl ester (2.0 g, 10.0 mmol, 1.3 equiv) and N-ethyl diisopropylamine (3.0 mL, 2.3 g, 17.7 mmol, 2.3 equiv) in acetonitrile (16 mL) was heated by microwave irradiation to 160° C. for 20 min. The reaction mixture was concentrated under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate. Suspension of the pre-purified material in ethyl acetate and filtration provided 0.89 g (36%) of the title compound. ¹H NMR (300 MHz, DMSO): δ 1.31-1.43 (m, 2H), 1.40 (s, 9H), 1.87-1.90 (m, 2H), 2.74-2.88 (m, 2H), 3.92-3.96 (m, 2H), 4.32 (br s, 1H), 7.52 (br s, 1H), 8.08 (s, 1H), 8.18 (s, 1H). MS (ISP): 319.3 [M+H]⁺.

Step 2

A solution of 4-(9H-purin-6-ylamino)-piperidine-1-carboxylic acid tert-butyl ester (0.89 g, 2.8 mmol) in 4 M HCl in dioxane (50 mL) was stirred at rt for 1 h. The solvent was removed under reduced pressure and the crude product used in the consecutive step without further purification assuming quantitative deprotection and formation of the dihydrochloride salt. MS (ISP): 219.4 [M+H]⁺.

The aldehyde intermediates D1 to D33 were prepared following literature precedents or in analogy to literature precedents or as described below.

Synthesis of Aldehyde Intermediates D1 to D25 to be used in Table 4 Intermediate D1 3-Ethoxy-4-fluoro-benzaldehyde

The title compound was prepared according to the procedure described for the synthesis of 4-chloro-3-ethoxy-benzaldehyde (intermediate D2, vide infra) starting from 4-fluoro-3-hydroxy-benzoic acid in 73% overall yield after purification by flash column chromatography on silica eluting with hexane/ethyl acetate (10:1). ¹H NMR (300 MHz, DMSO): δ 1.32 (t, J=7.0 Hz, 3H), 4.12 (q, J=7.0 Hz, 2H), 7.34-7.41 (m, 1H), 7.47-7.56 (m, 2H), 9.87 (s, 1H). MS (ISP): 186.1 [M+NH₄]⁺.

Intermediate D2 4-Chloro-3-ethoxy-benzaldehyde [CAS RN 85259-46-7]

To a solution of 4-chloro-3-hydroxy-benzoic acid (3.0 g, 17.4 mmol, 1.0 equiv) in DMF (15 mL) was added K₂CO₃ (4.81 g, 34.8 mmol, 2.0 equiv) and ethyl iodide (4.03 mL, 5.97 g, 38.2 mmol, 2.2 equiv). The reaction mixture was stirred for 6 h at rt, diluted with water (20 mL) and extracted with ethyl acetate (3×50 mL). The organic phases were dried over Na₂SO₄ and concentrated to afford 3.6 g (91%) of 4-chloro-3-ethoxy-benzoic acid ethyl ester. The crude ester was then dissolved in THF (20 mL) and cooled to −78° C. under Ar. A solution of diisobutylaluminium hydride (95 mL, 95.0 mmol, 6.0 equiv; 1.0 M solution in THF) was slowly added over a time period of 15 min, the cooling bath removed on completion of addition and the reaction allowed to warm up to 0° C. After stirring for 1 h, the reaction was cooled to −78° C. and the excess hydride quenched by cautious addition of a solution of 1 M HCl (10 mL). The mixture was brought to rt, the organic phase separated and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over Na₂SO₄ and concentrated by evaporation under reduced pressure providing 2.94 g (100%) of 4-chloro-3-ethoxy-benzyl alcohol. The crude alcohol (2.94 g, 15.75 mmol, 1.0 equiv) was dissolved in dichloromethane (15 mL) and activated MnO₂ (5.48 g, 63.0 mmol, 4.0 equiv) was added. The reaction mixture was stirred for 16 h, after which time the reaction was filtered through Hyflo Super Cel and concentrated. The residue was purified by flash column chromatography on silica eluting with heptane/ethyl acetate (4:1) to yield 1.51 g (52%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.51 (t, J=7.1 Hz, 3H), 4.19 (q, J=7.1 Hz, 2H), 7.37-7.42 (m, 2H), 7.55 (d, J=9.0 Hz, 1H), 9.94 (s, 1H).

Intermediate D3 3-Ethoxy-4-(1-ethyl-propoxy)-benzaldehyde

The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate D10, vide infra) by reaction of 3-ethoxy-4-hydroxy-benzaldehyde with 3-bromo-pentane in DMF using K₂CO₃ as base. MS (ISP): 237.1 [M+H]⁺.

Intermediate D4 3-Butoxy-4-methoxy-benzaldehyde

The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate D10, vide infra) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with 4-bromo-butane in DMF using K₂CO₃ as base. MS (ISP): 209.1 [M+H]⁺.

Intermediate D5 3,5-Diethoxy-benzaldehyde [CAS RN 120355-79-5]

The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate D10, vide infra) by reaction of 3,5-dihydroxybenzaldehyde with ethyl iodide in DMF using K₂CO₃ as base.

Intermediate D6 3-Hydroxy-5-isopropoxy-benzaldehyde

Isolated as a side-product in the synthesis of 3,5-diisopropoxy-benzaldehyde (intermediate D7, vide infra). ¹H NMR (300 MHz, CDCl₃): δ1.34 (d, J=6.1 Hz, 6H), 4.58 (hept, J=6.1 Hz, 1H), 6.28 (br s, 1H), 6.68-6.69 (m, 1H), 6.95-6.98 (m, 2H), 9.85 (s, 1H). MS (ISN): 179.1 [M−H]⁻.

Intermediate D7 3,5-Diisopropoxy-benzaldehyde [CAS RN 94169-64-9]

To a solution of 3,5-dihydroxy-benzaldehyde (5.0 g, 36.20 mmol, 1.0 equiv) in anhydrous DMF (30 mL) was added K₂CO₃ (15.0 g, 108.60 mmol, 3.0 equiv) and 2-bromo-propane (13.36 g, 10.20 mL, 108.60 mmol, 3.0 equiv) and the mixture stirred at 100° C. for 18 h. The K₂CO₃ was removed by filtration and the organic phase concentrated under reduced pressure. To the residue was added a sat. solution of NaCl (100 mL) and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄ and the product purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate affording 6.64 g (83%) of the title compound and 0.59 g (9%) of 3-hydroxy-5-isopropoxy-benzaldehyde (intermediate D6). ¹H NMR (300 MHz, CDCl₃): δ1.35 (d, J=6.1 Hz, 6H), 4.59 (hept, J=6.1 Hz, 1H), 6.66-6.68 (m, 1H), 6.96-6.97 (m, 2H), 9.88 (s, 1H). MS (ISP): 223.1 [M+H]⁺.

Intermediate D8 3-Ethoxy-4-iodo-5-methoxymethoxy-benzaldehyde [CAS RN 338451-02-8]

The title compound was prepared as described in WO 01/032 633 A1 (F. Hoffmann-La Roche A G).

Intermediate D9 2-Chloro-3,5-diethoxy-benzaldehyde

The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate D10, vide infra) by reaction of 2-chloro-3,5-dihydroxy benzaldehyde with iodoethane in DMF using K₂CO₃ as base. MS (ISP): 229.3 [M+H]⁺.

Intermediate D10 3-Ethoxy-4-methyl-benzaldehyde [CAS RN 157143-20-9]

The title compound was prepared by reaction of commercially available 3-hydroxy-4-methyl-benzaldehyde with ethyl iodide in DMF using K₂CO₃ as base in analogy to the procedure described in M. J. Ashton, D. C. Cook, G. Fenton, J.-A. Karlsson, M. N. Palfreyman, D. Raeburn, A. J. Ratcliffe, J. E. Souness, S. Thurairatnam and N. Vicker J. Med. Chem. 1994, 37, 1696-1703.

Intermediate D11 4-Methoxy-3-propoxy-benzaldehyde [CAS RN 5922-56-5]

The title compound was prepared by reaction of isovanillin with propyl iodide in DMF using K₂CO₃ as base in analogy to the preparation of 3-ethoxy-4-methyl-benzaldehyde (intermediate D10).

Intermediate D12 3-(2-Fluoro-ethoxy)-4-methoxy-benzaldehyde

To a solution of 3-hydroxy-4-methoxy-benzaldehyde (10.0 g, 66.0 mmol, 1.0 equiv) in anhydrous DMF (40 mL) was added K₂CO₃ (13.6 g, 99.0 mmol, 1.5 equiv) and 1-bromo-2-fluoro-ethane (9.2 mg, 72.0 mmol, 1.1 equiv) and the mixture stirred at rt for 48 h. The K₂CO₃ was removed by filtration and the organic phase concentrated under reduced pressure. To the residue was added a sat. solution of NaCl (100 mL) and the solution extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄ and the product crystallized from a mixture of isopropanol/diethylether to yield 12.69 g (97%) of the title compound. ¹H NMR (300 MHz, DMSO): δ 3.89 (s, 3H), 4.24-4.27 (m, 1H), 4.34-4.37 (m, 1H), 4.67-4.70 (m, 1H), 4.83-4.86 (m, 1H), 7.20 (d, J=8.4 Hz, 1H), 7.43 (d, J=1.9 Hz, 1H), 7.59 (dd, J=8.4 Hz, J=1.9 Hz, 1H), 9.84 (s, 1H). MS (ISP): 198.6 [M+H]⁺.

Intermediate D13 4-Methoxy-3-(2,2,2-trifluoro-ethoxy)-benzaldehyde [CAS RN 76588-84-6]

The title compound was prepared according to EP 0 251 294 B1 (Shionogi & Co.).

Intermediate D14 3-Allyloxy-4-methoxy-benzaldehyde [CAS RN 225939-36-6]

The title compound was prepared analogously to 3-ethoxy-4-methyl-benzaldehyde (intermediate D10) by reaction of 3-hydroxy-4-methoxy-benzaldehyde with allylbromide in DMF using K₂CO₃ as base (see also A. W. White, R. Almassy, A. H. Calvert, N. J. Curtin, R. J. Griffin, Z. Hostomsky, K. Maegley, D. R. Newell, S. Srinivasan and B. T. Golding J. Med. Chem. 2000, 43, 4084-4097).

Intermediate D15 3-Isobutoxy-4-methoxy-benzaldehyde [CAS RN 57724-26-2]

The title compound was prepared by reaction of isovanillin with 1-bromo-2-methyl propane as described in WO 04/000 806 A1 (Elbion A G).

Intermediate D16 8-Ethoxy-2,2-dimethyl-2H-chromene-6-carbaldehyde [CAS RN 210404-30-9]

The title compound was prepared according to WO 01/083 476 A1 (Hoffmann-La Roche A G).

Intermediate D17 4-Chloro-3,5-diethoxy-benzaldehyde

Step 1 4-Chloro-3,5-diethoxy-benzoic acid ethyl ester

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (5.1 g, 20.13 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick, Helv. Chim. Acta 1977, 60, 3025-3034) in water (40 mL) and 37% HCl (40 mL) at 0° C. was added sodium nitrite (1.67 g, 24.16 mmol, 1.2 equiv). After 10 min, copper(I) chloride (12.0 g, 120.81 mmol, 6.0 equiv) was added, the reaction mixture stirred for an additional 5 h at 0° C. and then the ice bath removed. After stirring for 18 h, the crude reaction mixture was adjusted to pH=8 by addition of a solution of 1 M NaOH and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄, concentrated by evaporation under reduced pressure and the crude material purified by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate providing 5.0 g (91%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.32 (t, J=7.0 Hz, 4H), 1.40 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 4.30 (q, J=7.0 Hz, 2H), 7.18 (s, 2H). ¹³C NMR (75 MHz, CDCl₃): δ13.33, 13.66, 60.29, 64.16, 105.75, 115.88, 128.25, 154.49, 165.01. MS (ISP): 273.3 [M+H]⁺.

Step 2 (4-Chloro-3,5-diethoxy-phenyl)-methanol

To a solution of 4-chloro-3,5-diethoxy-benzoic acid ethyl ester (5.0 g, 18.33 mmol, 1.0 equiv) in dichloromethane (25 mL) was added slowly over a time period of 15 min under slight cooling to −30° C. a solution of diisobutylaluminium hydride (55.0 mL, 55.00 mmol, 3.0 equiv; 1.0 M solution in THF). After 30 min, the excess hydride was quenched by cautious addition of methanol (10 mL) and water (2 mL). The mixture was stirred for 30 min, a solution of 1 M HCl was added and the aqueous layer extracted with ethyl acetate (3×100 mL). The combined organic phases were dried over MgSO₄ and concentrated by evaporation under reduced pressure providing 4.0 g (95%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.45 (t, J=7.0 Hz, 6H), 1.93 (br s, 1H), 4.09 (q, J=7.0 Hz, 4H), 4.62 (s, 2H), 6.57 (s, 2H). ¹³C NMR (75 MHz, CDCl₃): δ14.74, 64.96, 65.18, 104.30, 110.65, 140.29, 155.66. MS (ISP): 231.4 [M+H]⁺.

Step 3

To a solution of (4-chloro-3,5-diethoxy-phenyl)-methanol (4.0 g, 17.34 mmol, 1.0 equiv) in THF (40 mL) was added activated MnO₂ (15.08 g, 173.4 mmol, 10.0 equiv) and the reaction mixture stirred for 18 h at rt. Filtration through Hyflo Super Cel and purification of the crude material by silica column chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of heptane/ethyl acetate provided 3.7 g (92%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.50 (t, J=7.0 Hz, 6H), 4.19 (q, J=7.0 Hz, 4H), 7.07 (s, 2H), 9.89 (s, 1H). ¹³C NMR (75 MHz, CDCl₃): δ14.61, 65.22, 106.26, 118.64, 135.08, 156.22, 191.01. MS (EI): 229.4 [M]⁺.

Intermediate D18 4-Bromo-3,5-diethoxy-benzaldehyde [CAS RN 363166-11-4]

The title compound was prepared from 4-bromo-3,5-dihydroxy-benzoic acid as described in S. P. Dudek, H. D. Sikes and C. E. D. Chidsey J. Am. Chem. Soc. 2001, 123, 8033-8038.

Intermediate D19 3,5-Diethoxy-4-pyrrol-1-yl-benzaldehyde

Step 1 3,5-Diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (3.0 g, 11.84 mmol, 1.0 equiv; prepared as described in I. Kompis and A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in heptane (10 mL) and conc. acetic acid (0.2 mL) was added 2,5-dimethoxy-tetrahydro-furan (1.88 g, 14.21 mmol, 1.2 equiv). After heating to reflux for 5 h, a Dean-Stark apparatus was attached and the reaction mixture heated for an additional time period of 5 h. Filtration of the crude reaction mixture and crystallization at 0° C. from heptane provided 2.94 g (82%) of the title compound. ¹H NMR (300 MHz, DMSO): δ 1.15 (t, J=7.0 Hz, 6H), 1.27 (t, J=7.1 Hz, 3H), 3.98 (q, J=7.0 Hz, 4H), 4.28 (q, J=7.1 Hz, 2H), 6.07-6.08 (m, 2H), 6.73-6.74 (m, 2H), 7.22 (s, 2H). ¹³C NMR (75 MHz, DMSO): δ 14.11, 14.35, 61.06, 64.57, 106.87, 107.64, 122.61, 123.33, 129.29, 153.75, 165.06. MS (ISP): 303.4 [M+H]⁺.

Step 2

To a solution of 3,5-diethoxy-4-pyrrol-1-yl-benzoic acid ethyl ester (1.51 g, 4.98 mmol, 1.0 equiv) in toluene (5 mL) was added slowly over a time period of 15 min under slight cooling to 20° C. a solution of diisobutylaluminium hydride (8.9 mL, 12.45 mmol, 2.5 equiv; 20% solution in toluene). After 1 h, the excess hydride was quenched by cautious addition of water (10 mL) and a 28% solution of NaOH (2 mL). The mixture was stirred for 30 min and the organic phase filtered over Hyflo Super Cel. The aqueous layer was extracted with toluene (2×50 mL), the combined organic phases washed with a sat. solution of NaCl (2×50 mL) and concentrated by evaporation under reduced pressure to afford 1.30 g (100%) of (3,5-diethoxy-4-pyrrol-1-yl-phenyl)-methanol. The crude alcohol (1.30 g, 4.98 mmol, 1.0 equiv) was dissolved in toluene (20 mL) and activated MnO₂ (7.79 g, 89.5 mmol, 18.0 equiv) was added. The reaction mixture was heated to reflux for 7 h, after which time the reaction mixture was filtered through Hyflo Super Cel and concentrated yielding 1.15 g (89% yield) of the title compound. ¹H NMR (300 MHz, DMSO): δ 1.17 (t, J=7.0 Hz, 6H), 4.02 (q, J=7.0 Hz, 4H), 6.08-6.09 (m, 2H), 6.75-6.76 (m, 2H), 7.25 (s, 2H), 9.89 (s, 1H). MS (ISP): 260.1 [M+H]⁺.

Intermediate D20 3,5-Diethoxy-4-fluoro-benzaldehyde

Step 1 tert-Butyl-(4-fluoro-benzyloxy)-dimethyl-silane

To a solution of (4-fluoro-phenyl)-methanol (12.16 g, 96.4 mmol, 1.0 equiv) in anhydrous DMF (50 mL) at 0° C. under Ar was added imidazole (7.22 g, 106.1 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (15.99 g, 106.1 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na₂CO₃ (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na₂SO₄, concentrated by evaporation under reduced pressure yielding a brown oil that was purified by high vacuum distillation (bp 32-35° C. at 0.1 mbar) to give 23.0 g (99%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.84 (s, 9H), 4.60 (s, 2H), 6.89-6.94 (m, 2H), 7.16-7.20 (m, 2H). MS (EI): 183.1 [M-tert-Bu]⁺.

Step 2 5-(tert-Butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol

To a solution of tert-butyl-(4-fluoro-benzyloxy)-dimethyl-silane (5.00 g, 20.8 mmol, 1.0 equiv) in anhydrous THF (20 mL) was added at −78° C. under Ar a solution of sec-BuLi (17.6 mL, 22.8 mmol, 1.1 equiv; 1.3 M solution in hexane) within 30 min. Then a solution of trimethyl borate (2.37 mL, 2.20 g, 20.8 mmol, 1.0 equiv) in anhydrous THF (7.5 mL) was added slowly within 30 min and the cooling bath removed. A solution of conc. acetic acid (2.78 mL, 1.87 g, 31.2 mmol, 1.5 equiv) was slowly added followed by addition of a solution of 35% hydrogen peroxide in water (2.0 mL, 2.23 g, 22.9 mmol, 1.1 equiv) and the reaction mixture kept at 0° C. for 30 min. After stirring at rt for an additional 4 h, the reaction was extracted with diethyl ether (2×100 mL) and the combined organic phases washed with a solution of 10% NaOH (2×100 mL) and a sat. solution of NaCl (2×100 mL). The organic phase was dried over Na₂SO₄, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (19:1) providing 4.80 g (90%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.84 (s, 9H), 4.56 (s, 2H), 4.97 (br s, 1H), 6.68-6.72 (m, 1H), 6.87-6.94 (m, 2H). MS (EI): 256.2 [M]⁺.

Step 3 2-(tert-Butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene

To a solution of 5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (4.60 g, 17.9 mmol, 1.0 equiv) in anhydrous DMF (20 mL) at 0° C. under Ar was added imidazole (1.34 g, 19.7 mmol, 1.1 equiv) and tert-butyl-chloro-dimethyl-silane (2.97 g, 19.7 mmol, 1.1 equiv). After the addition was completed the cooling bath was removed and the reaction stirred for 18 h at rt. The reaction mixture was poured on ice, extracted with ethyl acetate (2×100 mL) and the combined organic phases washed with a sat. solution of Na₂CO₃ (2×100 mL) and NaCl (2×100 mL). The organic phase was dried over Na₂SO₄ and concentrated by evaporation under reduced pressure yielding 4.50 g (68%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.92 (s, 9H), 4.55 (s, 2H), 6.71-6.74 (m, 1H), 6.80-6.83 (m, 1H), 6.87-6.92 (m, 1H). MS (O): 370.2 [M]⁺.

Step 4 3-(tert-Butyl-dimethyl-silanyloxy)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol

To a solution of 2-(tert-butyl-dimethyl-silanyloxy)-4-(tert-butyl-dimethyl-silanyloxymethyl)-1-fluoro-benzene (23.70 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (130 mL) was added at −78° C. under Ar a solution of sec-BuLi (54.5 mL, 71.6 mmol, 1.1 equiv; 1.3 M solution in hexane) within 30 min. Then a solution of trimethyl borate (7.13 mL, 6.64 g, 63.9 mmol, 1.0 equiv) in anhydrous THF (30 mL) was added slowly within 30 min and the cooling bath removed. A solution of conc. acetic acid (5.49 mL, 5.76 g, 95.9 mmol, 1.5 equiv) was slowly added followed by addition of a solution of 35% hydrogen peroxide in water (6.2 mL, 6.83 g, 70.3 mmol, 1.1 equiv) and the reaction mixture kept at 0° C. for 30 min. After stirring at rt for an additional 4 h, the reaction was extracted with diethyl ether (2×100 mL) and the combined organic phases washed with a solution of 10% NaOH (2×100 mL) and a sat. solution of NaCl (2×100 mL). The organic phase was dried over Na₂SO₄, concentrated by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl acetate (19:1) providing 15.80 g (64%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.10 (s, 6H), 0.85 (s, 9H), 0.91 (s, 9H), 4.50 (s, 2H), 4.93 (br s, 1H), 6.37 (d, J=5.6 Hz, 1H), 6.47 (d, J=5.6 Hz, 1H). MS (EI): 329.2 [M-tert-Bu]⁺.

Step 5 tert-Butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane

To a solution of 3-(tert-butyl-dimethyl-silanyloxy)-5-(tert-butyl-dimethyl-silanyloxymethyl)-2-fluoro-phenol (5.80 g, 15.0 mmol, 1.0 equiv) in DMF (60 mL) was added K₂CO₃ (4.56 g, 33.0 mmol, 2.2 equiv) and ethyl bromide (2.46 mL, 3.60 g, 33.0 mmol, 2.2 equiv) and the reaction mixture stirred under Ar at 60° C. for 5 h. The K₂CO₃ was removed by filtration, the crude reaction mixture concentrated by evaporation under reduced pressure, the residue extracted with ethyl acetate (3×100 mL), the combined organic phases washed with water (2×100 ml) and dried over Na₂SO₄. The solvent was removed by evaporation under reduced pressure and the crude material purified with column chromatography on silica eluting with hexane/ethyl:acetate (99:1) providing 3.10 g (63%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ0.00 (s, 6H), 0.85 (s, 9H), 1.33 (t, J=7.0 Hz, 6H), 4.00 (q, J=7.0 Hz, 4H), 4.55 (s, 2H), 6.47 (d, J=6.8 Hz, 2H). MS (ISP): 329.3 [M+H]⁺.

Step 6 (3,5-Diethoxy-4-fluoro-phenyl)-methanol

To a solution of tert-butyl-(3,5-diethoxy-4-fluoro-benzyloxy)-dimethyl-silane (1.20 g, 3.65 mmol, 1.0 equiv) in methanol (8 mL) was added Dowex 50W-X8 (0.33 g, cation exchange resin) and the reaction mixture stirred under Ar at rt for 22 h. The resin was removed by filtration and the reaction mixture concentrated by evaporation under reduced pressure yielding the title compound in quantitative yield (0.78 g). ¹H NMR (400 MHz, CDCl₃): δ1.34 (t, J=7.0 Hz, 6H), 1.57 (t, J=5.4 Hz, 1H), 4.01 (q, J=7.0 Hz, 4H), 4.51 (d, J=5.4 Hz, 2H), 6.51 (d, J=6.8 Hz, 2H). MS (EI): 214.2 [M]⁺.

Step 7

To a solution of (3,5-diethoxy-4-fluoro-phenyl)-methanol (2.30 g, 10.7 mmol, 1.0 equiv) in 1,2-dichloroethane (50 mL) was added activated MnO₂ (2.89 g, 33.3 mmol, 3.1 equiv). The reaction mixture was stirred for 21 h at 50° C. and then filtered through Hyflo Super Cel providing after evaporation of the solvent under reduced pressure 1.90 g (83%) of the title compound. ¹H NMR (400 MHz, CDCl₃): δ1.38 (t, J=7.0 Hz, 6H), 4.09 (q, J=7.0 Hz, 4H), 7.04 (d, J=7.2 Hz, 2H), 9.75 (s, 1H). MS (EI): 212.1 [M]⁺.

Intermediate D21 3-Ethoxy-4-methoxy-5-nitro benzaldehyde

To a solution of 3-ethoxy-4-methoxybenzaldehyde (6.0 g, 33.3 mmol, 1.0 equiv; commercially available) in diethyl ether (50 mL) was added dropwise nitric acid 65% (4.12 mL, 5.81 g, 59.9 mmol, 1.8 equiv) over a period of 30 min at rt. After the addition was completed the reaction mixture was heated to reflux for 4 h. The reaction product precipitated out of solution, was filtered off, washed with cold diethyl ether (3×20 mL) and dried yielding 5.85 g (78%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.53 (t, J=7.0 Hz, 3H), 4.04 (s, 3H), 4.26 (q, J=7.0 Hz, 2H), 7.37 (s, 1H), 7.61 (s, 1H), 10.40 (s, 1H). ¹³C NMR (75 MHz, CDCl₃): δ14.34, 56.68, 65.35, 107.31, 110.48, 125.52, 143.56, 152.54, 152.70, 187.60. MS (ISP): 225.9 [M+H]⁺.

Intermediate D22 3-Ethylamino-4-methoxy-benzaldehyde

Through a solution of 2-(3-bromo-4-methoxy-phenyl)-[1,3]dioxolane (1.2 g, 4.63 mmol, 1.0 equiv; prepared as described in WO 01/74775 A1, Sanofi-Synthelabo) in toluene (6 mL) was bubbled ethylamine for 10 min. To this solution was added KOtert-Bu (0.67 g, 6.95 mmol, 1.5 equiv), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (0.029 g, 0.046 mmol, 0.01 equiv) and tris(dibenzylideneacetone)-dipalladium(0) (0.021 g, 0.023 mmol, 0.005 equiv) and the solution heated to 110° C. under microwave irradiation for 20 min. A few drops of a solution of 37% HCl were added and the reaction mixture heated again under microwave irradiation to 100° C. for 5 min. Evaporation of the solvent and purification of the crude reaction product by column chromatography on silica eluting with hexane/ethyl acetate (7:3) provided 0.52 g (63%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.24 (t, J=7.1 Hz, 3H), 3.16 (q, J=7.1 Hz, 2H), 3.86 (s, 3H), 4.17 (br s, 1H), 6.78 (d, J=8.1 Hz, 1H), 7.01 (d, J=1.9 Hz, 1H), 7.13 (dd, J=8.1 Hz, J=1.9 Hz, 1H), 9.75 (s, 1H). MS (ISP): 179.9 [M+H]⁺.

Intermediate D23 4-Amino-3,5-diethoxy-benzaldehyde

Step 1 (4-Amino-3,5-diethoxy-phenyl)-methanol

To a solution of 4-amino-3,5-diethoxy-benzoic acid ethyl ester (2.8 g, 11.05 mmol, 1.0 equiv; prepared as described in I. Kompis, A. Wick Helv. Chim. Acta 1977, 60, 3025-3034) in dichloromethane (50 mL) at 0° C. under Ar was slowly added diisobutylaluminium hydride (27.6 mL, 27.64 mmol, 2.5 equiv; 1.0 M solution in dichloromethane) over a time period of 15 min and the cooling bath removed on completion of addition. After stirring for 18 h, the excess hydride was quenched by cautious addition of a sat. solution of potassium sodium tartrate (10 mL). The solidified mixture was extracted with dichloromethane (5×200 mL) and THF (2×150 mL), the combined organic phases washed with water (3×100 mL), dried over MgSO₄, concentrated by evaporation under reduced pressure and the crude material purified by column chromatography on silica eluting with a gradient of heptane/ethyl acetate (4:1→1:1) providing 1.10 g (47%) of the title compound. ¹H NMR (300 MHz, CDCl₃): δ1.42 (t, J=7.0 Hz, 3H), 3.82 (br s, 2H), 4.05 (q, J=7.0 Hz, 2H), 4.54 (s, 2H), 6.50 (s, 2H). ¹³C NMR (75 MHz, CDCl₃): δ15.03, 64.21, 66.00, 104.51, 125.44, 129.89, 146.71. MS (ISP): 211.9 [M+H]⁺.

Step 2

To a solution of (4-amino-3,5-diethoxy-phenyl)-methanol (0.79 g, 3.74 mmol, 1.0 equiv) in DMF (20 mL) was added activated MnO₂ (1.63 g, 18.70 mmol, 5.0 equiv). The reaction mixture was stirred for 24 h at rt, filtered through Hyflo Super Cel, the filtrate extracted with ethyl acetate (3×50 mL) and the combined organic phases dried over MgSO₄ providing 0.69 g (88%) of the title compound. ¹H NMR (300 MHz, DMSO): δ 1.46 (t, J=7.0 Hz, 3H), 4.15 (q, J=7.0 Hz, 2H), 4.50 (br s, 2H), 7.04 (s, 2H), 9.70 (s, 1H). MS (ISP): 210.0 [M+H]⁺.

Intermediate D24 Methanesulfonic acid 2-ethoxy-4-formyl-phenyl ester

To a solution of 3-ethoxy-4-hydroxybenzaldehyde (3.0 g, 18.1 mmol, 1.0 equiv) and N,N-dimethylaminopyridine (2.87 g, 23.5 mmol, 1.3 equiv) in dichloromethane (10 mL) under Ar at 0° C. was added methanesulfonyl chloride (1.68 mL, 2.48 g, 21.7 mmol, 1.2 equiv). After the reaction mixture was stirred for 1 h, water (100 mL) was added, the solution extracted with dichloromethane (3×50 mL) and the combined organic phases dried over MgSO₄. Removal of the solvent by evaporation under reduced pressure provided the title compound in quantitative yield (4.8 g). ¹H NMR (300 MHz, CDCl₃): δ1.42 (t, J=7.0 Hz, 3H), 3.19 (s, 3H), 4.14 (q, J=7.0 Hz, 2H), 7.41 (s, 2H), 7.45 (s, 1H), 9.89 (s, 1H). ¹³C NMR (75 MHz, CDCl₃): δ14.53, 38.94, 64.99, 112.20, 124.38, 125.17, 136.01, 142.92, 151.63, 190.65. MS (ISP): 245.2 [M+H]⁺.

Intermediate D25 3-Benzyloxy-5-ethoxy-benzaldehyde [CAS RN 227023-81-6]

The title compound was prepared according to EP 0921 116 A1 (F. Hoffmann-La Roche A G).

Examples 35 to 216

According to the procedure described for the synthesis of example 34/step 3 further pyrimidine, quinazoline and purine derivatives have been synthesized from (2-chloro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C1), (2-chloro-6-methyl-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C2), (2,6-dichloro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C3), 4-methoxy-6-(piperidin-4-ylamino)-pyrimidin-2-ol dihydrochloride (intermediate C4), 2-chloro-6-(piperidin-4-ylamino)-pyrimidine-4-carboxylic acid methyl ester dihydrochloride (intermediate C5), N-[2-chloro-6-(piperidin-4-ylamino)-pyrimidin-4-yl]-acetamide dihydrochloride (intermediate C6), (2-chloro-5-fluoro-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C7), (2-chloro-5-methoxy-pyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C8), (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C9), [2,4-dichloro-6-(piperidin-4-ylamino)-pyrimidin-5-yl]-acetic acid ethyl ester dihydrochloride (intermediate C10), piperidin-4-yl-(2,5,6-trichloro-pyrimidin-4-yl)-amine dihydrochloride (intermediate C11), (7-chloro-quinazolin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C12), (2-chloro-6,7-dimethoxy-quinazolin-4-yl)-piperidin-4-yl-amine dihydrochloride (intermediate C13) and piperidin-4-yl-(9H-purin-6-yl)-amine dihydrochloride (intermediate C14) and the respective benzaldehyde intermediate as indicated in Table 4. The results are compiled in Table 4 and comprise example 35 to example 216.

TABLE 4 [M + H]⁺ or [M − H]⁻ No MW Compound Name Starting Materials found 35 364.85 (2-chloro-pyrimidin-4- (2-chloro-pyrimidin-4-yl)- ISP yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ fluoro-benzyl)-piperidin- dihydrochloride (intermediate 365.2 4-yl]-amine C1) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 36 381.31 [1-(4-chloro-3-ethoxy- (2-chloro-pyrimidin-4-yl)- ISP benzyl)-piperidin-4-yl]- piperidin-4-yl-amine [M + H]⁺ (2-chloro-pyrimidin-4- dihydrochloride (intermediate 381.3 yl)-amine C1) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 37 362.86 4-[4-(2-chloro- (2-chloro-pyrimidin-4-yl)- ISP pyrimidin-4-ylamino)- piperidin-4-yl-amine [M + H]⁺ piperidin-1-ylmethyl]-2- dihydrochloride (intermediate 363.5 ethoxy-phenol C1) and 3-ethoxy-4-hydroxy- benzaldehyde (commercially available) 38 404.94 (2-chloro-pyrimidin-4- (2-chloro-pyrimidin-4-yl)- ISP yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ isopropoxy-benzyl)- dihydrochloride (intermediate 405.4 piperidin-4-yl]-amine C1) and 3-ethoxy-4-isopropoxy- benzaldehyde (commercially available) 39 433.00 (2-chloro-pyrimidin-4- (2-chloro-pyrimidin-4-yl)- ISP yl)-{1-[3-ethoxy-4-(1- piperidin-4-yl-amine [M + H]⁺ ethyl-propoxy)-benzyl]- dihydrochloride (intermediate 433.4 piperidin-4-yl}-amine C1) and 3-ethoxy-4-(1-ethyl- propoxy)-benzaldehyde (intermediate D3) 40 404.94 [1-(3-butoxy-4- (2-chloro-pyrimidin-4-yl)- ISP methoxy-benzyl)- piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 405.4 chloro-pyrimidin-4-yl)- C1) and 3-butoxy-4-methoxy- amine benzaldehyde (intermediate D4) 41 390.91 (2-chloro-pyrimidin-4- (2-chloro-pyrimidin-4-yl)- ISP yl)-[1-(3,5-diethoxy- piperidin-4-yl-amine [M + H]⁺ benzyl)-piperidin-4-yl]- dihydrochloride (intermediate 391.2 amine C1) and 3,5-diethoxy- benzaldehyde (intermediate D5) 42 376.89 3-[4-(2-chloro- (2-chloro-pyrimidin-4-yl)- ISP pyrimidin-4-ylamino)- piperidin-4-yl-amine [M + H]⁺ piperidin-1-ylmethyl]-5- dihydrochloride (intermediate 377.3 isopropoxy-phenol C1) and 3-hydroxy-5- isopropoxy-benzaldehyde (intermediate D6) 43 418.97 (2-chloro-pyrimidin-4- (2-chloro-pyrimidin-4-yl)- ISP yl)-[1-(3,5-diisopropoxy- piperidin-4-yl-amine [M + H]⁺ benzyl)-piperidin-4-yl]- dihydrochloride (intermediate 419.2 amine C1) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 44 532.81 (2-chloro-pyrimidin-4- (2-chloro-pyrimidin-4-yl)- ISP yl)-[1-(3-ethoxy-4-iodo- piperidin-4-yl-amine [M + H]⁺ 5-methoxymethoxy- dihydrochloride (intermediate 533.1 benzyl)-piperidin-4-yl]- C1) and 3-ethoxy-4-iodo-5- amine methoxymethoxy-benzaldehyde (intermediate D8) 45 425.36 [1-(2-chloro-3,5- (2-chloro-pyrimidin-4-yl)- ISP diethoxy-benzyl)- piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 425.2 chloro-pyrimidin-4-yl)- C1) and 2-chloro-3,5-diethoxy- amine benzaldehyde (intermediate D9) 46 374.92 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3- 4-yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-4-methyl- dihydrochloride (intermediate 375.3 benzyl)-piperidin-4-yl]- C2) and 3-ethoxy-4-methyl- amine benzaldehyde (intermediate D10) 47 378.88 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3- 4-yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-4-fluoro-benzyl)- dihydrochloride (intermediate 379.3 piperidin-4-yl]-amine C2) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 48 395.33 [1-(4-chloro-3-ethoxy- (2-chloro-6-methyl-pyrimidin- ISP benzyl)-piperidin-4-yl]- 4-yl)-piperidin-4-yl-amine [M + H]⁺ (2-chloro-6-methyl- dihydrochloride (intermediate 395.2 pyrimidin-4-yl)-amine C2) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 49 404.94 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3,4- 4-yl)-piperidin-4-yl-amine [M + H]⁺ diethoxy-benzyl)- dihydrochloride (intermediate 405.4 piperidin-4-yl]-amine C2) and 3,4-diethoxy- benzaldehyde (commercially available) 50 418.97 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3- 4-yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-4-isopropoxy- dihydrochloride (intermediate 419.2 benzyl)-piperidin-4-yl]- C2) and 3-ethoxy-4-isopropoxy- amine benzaldehyde (commercially available) 51 404.94 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(4- 4-yl)-piperidin-4-yl-amine [M + H]⁺ methoxy-3-propoxy- dihydrochloride (intermediate 405.3 benzyl)-piperidin-4-yl]- C2) and 4-methoxy-3-propoxy- amine benzaldehyde (intermediate D11) 52 408.90 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-{1-[3- 4-yl)-piperidin-4-yl-amine [M + H]⁺ (2-fluoro-ethoxy)-4- dihydrochloride (intermediate 409.2 methoxy-benzyl]- C2) and 3-(2-fluoro-ethoxy)-4- piperidin-4-yl}-amine methoxy-benzaldehyde (intermediate D12) 53 444.88 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-{1-[4- 4-yl)-piperidin-4-yl-amine [M + H]⁺ methoxy-3-(2,2,2- dihydrochloride (intermediate 445.2 trifluoro-ethoxy)- C2) and 4-methoxy-3-(2,2,2- benzyl]-piperidin-4-yl}- trifluoro-ethoxy)-benzaldehyde amine (intermediate D13) 54 402.93 [1-(3-allyloxy-4- (2-chloro-6-methyl-pyrimidin- ISP methoxy-benzyl)- 4-yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 403.3 chloro-6-methyl- C2) and 3-allyloxy-4-methoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D14) 55 418.97 [1-(3-butoxy-4- (2-chloro-6-methyl-pyrimidin- ISP methoxy-benzyl)- 4-yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 419.2 chloro-6-methyl- C2) and 3-butoxy-4-methoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D4) 56 418.97 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3- 4-yl)-piperidin-4-yl-amine [M + H]⁺ isobutoxy-4-methoxy- dihydrochloride (intermediate 419.2 benzyl)-piperidin-4-yl]- C2) and 3-isobutoxy-4- amine methoxy-benzaldehyde (intermediate D15) 57 442.99 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(8- 4-yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-2,2-dimethyl-2H- dihydrochloride (intermediate 443.3 chromen-6-ylmethyl)- C2) and 8-ethoxy-2,2-dimethyl- piperidin-4-yl]-amine 2H-chromene-6-carbaldehyde (intermediate D16) 58 404.94 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3,5- 4-yl)-piperidin-4-yl-amine [M + H]⁺ diethoxy-benzyl)- dihydrochloride (intermediate 405.4 piperidin-4-yl]-amine C2) and 3,5-diethoxy- benzaldehyde (intermediate D5) 59 433.00 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3,5- 4-yl)-piperidin-4-yl-amine [M + H]⁺ diisopropoxy-benzyl)- dihydrochloride (intermediate 433.3 piperidin-4-yl]-amine C2) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 60 439.39 [1-(4-chloro-3,5- (2-chloro-6-methyl-pyrimidin- ISP diethoxy-benzyl)- 4-yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 439.2 chloro-6-methyl- C2) and 4-chloro-3,5-diethoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D17) 61 483.84 [1-(4-bromo-3,5- (2-chloro-6-methyl-pyrimidin- ISP diethoxy-benzyl)- 4-yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 485.2 chloro-6-methyl- C2) and 4-bromo-3,5-diethoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D18) 62 470.02 (2-chloro-6-methyl- (2-chloro-6-methyl-pyrimidin- ISP pyrimidin-4-yl)-[1-(3,5- 4-yl)-piperidin-4-yl-amine [M + H]⁺ diethoxy-4-pyrrol-1-yl- dihydrochloride (intermediate 470.3 benzyl)-piperidin-4-yl]- C2) and 3,5-diethoxy-4-pyrrol- amine 1-yl-benzaldehyde (intermediate D19) 63 395.33 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ methyl-benzyl)- dihydrochloride (intermediate 395.3 piperidin-4-yl]-amine C3) and 3-ethoxy-4-methyl- benzaldehyde (intermediate D10) 64 399.30 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ fluoro-benzyl)-piperidin- dihydrochloride (intermediate 399.2 4-yl]-amine C3) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 65 415.75 [1-(4-chloro-3-ethoxy- (2,6-dichloro-pyrimidin-4-yl)- ISP benzyl)-piperidin-4-yl]- piperidin-4-yl-amine [M + H]⁺ (2,6-dichloro-pyrimidin- dihydrochloride (intermediate 417.2 4-yl)-amine C3) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 66 397.31 4-[4-(2,6-dichloro- (2,6-dichloro-pyrimidin-4-yl)- ISP pyrimidin-4-ylamino)- piperidin-4-yl-amine [M + H]⁺ piperidin-1-ylmethyl]-2- dihydrochloride (intermediate 397.2 ethoxy-phenol C3) and 3-ethoxy-4-hydroxy- benzaldehyde (commercially available) 67 411.33 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ methoxy-benzyl)- dihydrochloride (intermediate 411.3 piperidin-4-yl]-amine C3) and 3-ethoxy-4-methoxy- benzaldehyde (commercially available) 68 439.39 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ isopropoxy-benzyl)- dihydrochloride (intermediate 439.2 piperidin-4-yl]-amine C3) and 3-ethoxy-4-isopropoxy- benzaldehyde (commercially available) 69 467.44 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-{1-[3-ethoxy-4-(1- piperidin-4-yl-amine [M + H]⁺ ethyl-propoxy)-benzyl]- dihydrochloride (intermediate 467.2 piperidin-4-yl}-amine C3) and 3-ethoxy-4-(1-ethyl- propoxy)-benzaldehyde (intermediate D3) 70 429.32 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-{1-[3-(2-fluoro- piperidin-4-yl-amine [M + H]⁺ ethoxy)-4-methoxy- dihydrochloride (intermediate 429.2 benzyl]-piperidin-4-yl}- C3) and 3-(2-fluoro-ethoxy)-4- amine methoxy-benzaldehyde (intermediate D12) 71 423.34 [1-(3-allyloxy-4- (2,6-dichloro-pyrimidin-4-yl)- ISP methoxy-benzyl)- piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2,6- dihydrochloride (intermediate 423.2 dichloro-pyrimidin-4- C3) and 3-allyloxy-4-methoxy- yl)-amine benzaldehyde (intermediate D14) 72 439.39 [1-(3-butoxy-4- (2,6-dichloro-pyrimidin-4-yl)- ISP methoxy-benzyl)- piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2,6- dihydrochloride (intermediate 439.2 dichloro-pyrimidin-4- C3) and 3-butoxy-4-methoxy- yl)-amine benzaldehyde (intermediate D4) 73 439.39 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3-isobutoxy-4- piperidin-4-yl-amine [M + H]⁺ methoxy-benzyl)- dihydrochloride (intermediate 439.2 piperidin-4-yl]-amine C3) and 3-isobutoxy-4- methoxy-benzaldehyde (intermediate D15) 74 463.41 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(8-ethoxy-2,2- piperidin-4-yl-amine [M + H]⁺ dimethyl-2H-chromen- dihydrochloride (intermediate 463.2 6-ylmethyl)-piperidin-4- C3) and 8-ethoxy-2,2-dimethyl- yl]-amine 2H-chromene-6-carbaldehyde (intermediate D16) 75 425.36 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3,5-diethoxy- piperidin-4-yl-amine [M + H]⁺ benzyl)-piperidin-4-yl]- dihydrochloride (intermediate 425.2 amine C3) and 3,5-diethoxy- benzaldehyde (intermediate D5) 76 411.33 3-[4-(2,6-dichloro- (2,6-dichloro-pyrimidin-4-yl)- ISP pyrimidin-4-ylamino)- piperidin-4-yl-amine [M + H]⁺ piperidin-1-ylmethyl]-5- dihydrochloride (intermediate 411.3 isopropoxy-phenol C3) and 3-hydroxy-5- isopropoxy-benzaldehyde (intermediate D6) 77 453.41 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3,5- piperidin-4-yl-amine [M + H]⁺ diisopropoxy-benzyl)- dihydrochloride (intermediate 453.2 piperidin-4-yl]-amine C3) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 78 443.35 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3,5-diethoxy-4- piperidin-4-yl-amine [M + H]⁺ fluoro-benzyl)-piperidin- dihydrochloride (intermediate 443.3 4-yl]-amine C3) and 3,5-diethoxy-4-fluoro- benzaldehyde (intermediate D20) 79 459.80 [1-(4-chloro-3,5- (2,6-dichloro-pyrimidin-4-yl)- ISP diethoxy-benzyl)- piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2,6- dihydrochloride (intermediate 459.2 dichloro-pyrimidin-4- C3) and 4-chloro-3,5-diethoxy- yl)-amine benzaldehyde (intermediate D17) 80 504.26 [1-(4-bromo-3,5- (2,6-dichloro-pyrimidin-4-yl)- ISP diethoxy-benzyl)- piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2,6- dihydrochloride (intermediate 505.0 dichloro-pyrimidin-4- C3) and 4-bromo-3,5-diethoxy- yl)-amine benzaldehyde (intermediate D18) 81 490.43 (2,6-dichloro-pyrimidin- (2,6-dichloro-pyrimidin-4-yl)- ISP 4-yl)-[1-(3,5-diethoxy-4- piperidin-4-yl-amine [M + H]⁺ pyrrol-1-yl-benzyl)- dihydrochloride (intermediate 490.1 piperidin-4-yl]-amine C3) and 3,5-diethoxy-4-pyrrol- 1-yl-benzaldehyde (intermediate D19) 82 372.47 4-[1-(3-ethoxy-4- 4-methoxy-6-(piperidin-4- ISP methyl-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 373.3 methoxy-pyrimidin-2-ol C4) and 3-ethoxy-4-methyl- benzaldehyde (intermediate D10) 83 376.43 4-[1-(3-ethoxy-4-fluoro- 4-methoxy-6-(piperidin-4- ISP benzyl)-piperidin-4- ylamino)-pyrimidin-2-ol [M + H]⁺ ylamino]-6-methoxy- dihydrochloride (intermediate 377.3 pyrimidin-2-ol C4) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 84 392.89 4-[1-(4-chloro-3-ethoxy- 4-methoxy-6-(piperidin-4- ISP benzyl)-piperidin-4- ylamino)-pyrimidin-2-ol [M + H]⁺ ylamino]-6-methoxy- dihydrochloride (intermediate 393.2 pyrimidin-2-ol C4) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 85 374.44 4-[1-(3-ethoxy-4- 4-methoxy-6-(piperidin-4- ISP hydroxy-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 375.3 methoxy-pyrimidin-2-ol C4) and 3-ethoxy-4-hydroxy- benzaldehyde (commercially available) 86 388.47 4-[1-(3-ethoxy-4- 4-methoxy-6-(piperidin-4- ISP methoxy-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 389.3 methoxy-pyrimidin-2-ol C4) and 3-ethoxy-4-methoxy- benzaldehyde (commercially available) 87 416.52 4-[1-(3-ethoxy-4- 4-methoxy-6-(piperidin-4- ISP isopropoxy-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 417.3 methoxy-pyrimidin-2-ol C4) and 3-ethoxy-4-isopropoxy- benzaldehyde (commercially available) 88 402.49 4-methoxy-6-[1-(4- 4-methoxy-6-(piperidin-4- ISP methoxy-3-propoxy- ylamino)-pyrimidin-2-ol [M + H]⁺ benzyl)-piperidin-4- dihydrochloride (intermediate 403.4 ylamino]-pyrimidin-2-ol C4) and 4-methoxy-3-propoxy- benzaldehyde (intermediate D11) 89 406.46 4-{1-[3-(2-fluoro- 4-methoxy-6-(piperidin-4- ISP ethoxy)-4-methoxy ylamino)-pyrimidin-2-ol [M + H]⁺ benzyl]-piperidin-4- dihydrochloride (intermediate 407.4 ylamino}-6-methoxy- C4) and 3-(2-fluoro-ethoxy)-4- pyrimidin-2-ol methoxy-benzaldehyde (intermediate D12) 90 400.48 4-[1-(3-allyloxy-4- 4-methoxy-6-(piperidin-4- ISP methoxy-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 401.3 methoxy-pyrimidin-2-ol C4) and 3-allyloxy-4-methoxy- benzaldehyde (intermediate D14) 91 416.52 4-[1-(3-butoxy-4- 4-methoxy-6-(piperidin-4- ISP methoxy-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 417.3 methoxy-pyrimidin-2-ol C4) and 3-butoxy-4-methoxy- benzaldehyde (intermediate D4) 92 416.52 4-[1-(3-isobutoxy-4- 4-methoxy-6-(piperidin-4- ISP methoxy-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 417.3 methoxy-pyrimidin-2-ol C4) and 3-isobutoxy-4- methoxy-benzaldehyde (intermediate D15) 93 440.54 4-[1-(8-ethoxy-2,2- 4-methoxy-6-(piperidin-4- ISP dimethyl-2H-chromen- ylamino)-pyrimidin-2-ol [M + H]⁺ 6-ylmethyl)-piperidin-4- dihydrochloride (intermediate 441.3 ylamino]-6-methoxy- C4) and 8-ethoxy-2,2-dimethyl- pyrimidin-2-ol 2H-chromene-6-carbaldehyde (intermediate D16) 94 402.49 4-[1-(3,5-diethoxy- 4-methoxy-6-(piperidin-4- ISP benzyl)-piperidin-4- ylamino)-pyrimidin-2-ol [M + H]⁺ ylamino]-6-methoxy- dihydrochloride (intermediate 403.4 pyrimidin-2-ol C4) and 3,5-diethoxy- benzaldehyde (intermediate D5) 95 430.55 4-[1-(3,5-diisopropoxy- 4-methoxy-6-(piperidin-4- ISP benzyl)-piperidin-4- ylamino)-pyrimidin-2-ol [M + H]⁺ ylamino]-6-methoxy- dihydrochloride (intermediate 431.4 pyrimidin-2-ol C4) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 96 420.48 4-[1-(3,5-diethoxy-4- 4-methoxy-6-(piperidin-4- ISP fluoro-benzyl)-piperidin- ylamino)-pyrimidin-2-ol [M + H]⁺ 4-ylamino]-6-methoxy- dihydrochloride (intermediate 421.3 pyrimidin-2-ol C4) and 3,5-diethoxy-4-fluoro- benzaldehyde (intermediate D20) 97 436.94 4-[1-(4-chloro-3,5- 4-methoxy-6-(piperidin-4- ISP diethoxy-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 437.3 methoxy-pyrimidin-2-ol C4) and 4-chloro-3,5-diethoxy- benzaldehyde (intermediate D17) 98 467.57 4-[1-(3,5-diethoxy-4- 4-methoxy-6-(piperidin-4- ISP pyrrol-1-yl-benzyl)- ylamino)-pyrimidin-2-ol [M + H]⁺ piperidin-4-ylamino]-6- dihydrochloride (intermediate 468.4 methoxy-pyrimidin-2-ol C4) and 3,5-diethoxy-4-pyrrol- 1-yl-benzaldehyde (intermediate D19) 99 418.92 2-chloro-6-[1-(3-ethoxy- 2-chloro-6-(piperidin-4- ESI 4-methyl-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]- carboxylic acid methyl ester 419.7 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 3-ethoxy-4-methyl- benzaldehyde (intermediate D10) 100 422.89 2-chloro-6-[1-(3-ethoxy- 2-chloro-6-(piperidin-4- ISP 4-fluoro-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]- carboxylic acid methyl ester 423.2 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 101 439.34 2-chloro-6-[1-(4-chloro- 2-chloro-6-(piperidin-4- ISP 3-ethoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]- carboxylic acid methyl ester 439.2 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 102 434.92 2-chloro-6-[1-(3-ethoxy- 2-chloro-6-(piperidin-4- ESI 4-methoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]- carboxylic acid methyl ester 434.7 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 3-ethoxy-4-methoxy- benzaldehyde (commercially available) 103 462.98 2-chloro-6-[1-(3-ethoxy- 2-chloro-6-(piperidin-4- ISP 4-isopropoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]- carboxylic acid methyl ester 463.2 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 3-ethoxy-4-isopropoxy- benzaldehyde (commercially available) 104 452.91 2-chloro-6-{1-[3-(2- 2-chloro-6-(piperidin-4- ESI fluoro-ethoxy)-4- ylamino)-pyrimidine-4- [M + H]⁺ methoxy-benzyl]- carboxylic acid methyl ester 452.7 piperidin-4-ylamino}- dihydrochloride_(intermediate pyrimidine-4-carboxylic C5) and 3-(2-fluoro-ethoxy)-4- acid methyl ester methoxy-benzaldehyde (intermediate D12) 105 446.93 6-[1-(3-allyloxy-4- 2-chloro-6-(piperidin-4- ESI methoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]-2- carboxylic acid methyl ester 446.7 chloro-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3-allyloxy-4-methoxy- ester benzaldehyde (intermediate D14) 106 462.98 6-[1-(3-butoxy-4- 2-chloro-6-(piperidin-4- ESI methoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]-2- carboxylic acid methyl ester 462.8 chloro-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3-butoxy-4-methoxy- ester benzaldehyde (intermediate D4) 107 462.98 2-chloro-6-[1-(3- 2-chloro-6-(piperidin-4- ISP isobutoxy-4-methoxy- ylamino)-pyrimidine-4- [M + H]⁺ benzyl)-piperidin-4- carboxylic acid methyl ester 463.2 ylamino]-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3-isobutoxy-4- ester methoxy-benzaldehyde (intermediate D15) 108 487.00 2-chloro-6-[1-(8-ethoxy- 2-chloro-6-(piperidin-4- ISP 2,2-dimethyl-2H- ylamino)-pyrimidine-4- [M + H]⁺ chromen-6-ylmethyl)- carboxylic acid methyl ester 487.3 piperidin-4-ylamino]- dihydrochloride_(intermediate pyrimidine-4-carboxylic C5) and 8-ethoxy-2,2-dimethyl- acid methyl ester 2H-chromene-6-carbaldehyde (intermediate D16) 109 448.95 2-chloro-6-[1-(3,5- 2-chloro-6-(piperidin-4- ESI diethoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]- carboxylic acid methyl ester 448.7 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 3,5-diethoxy- benzaldehyde (intermediate D5) 110 434.92 2-chloro-6-[1-(3- 2-chloro-6-(piperidin-4- ESI hydroxy-5-isopropoxy- ylamino)-pyrimidine-4- [M + H]⁺ benzyl)-piperidin-4- carboxylic acid methyl ester 434.7 ylamino]-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3-hydroxy-5- ester isopropoxy-benzaldehyde (intermediate D6) 111 477.00 2-chloro-6-[1-(3,5- 2-chloro-6-(piperidin-4- ESI diisopropoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]- carboxylic acid methyl ester 476.8 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 112 466.94 2-chloro-6-[1-(3,5- 2-chloro-6-(piperidin-4- ISP diethoxy-4-fluoro- ylamino)-pyrimidine-4- [M + H]⁺ benzyl)-piperidin-4- carboxylic acid methyl ester 467.3 ylamino]-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3,5-diethoxy-4-fluoro- ester benzaldehyde (intermediate D20) 113 527.84 6-[1-(4-bromo-3,5- 2-chloro-6-(piperidin-4- ESI diethoxy-benzyl)- ylamino)-pyrimidine-4- [M + H]⁺ piperidin-4-ylamino]-2- carboxylic acid methyl ester 528.7 chloro-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 4-bromo-3,5-diethoxy- ester benzaldehyde (intermediate D18) 114 590.84 2-chloro-6-[1-(3-ethoxy- 2-chloro-6-(piperidin-4- ESI 4-iodo-5- ylamino)-pyrimidine-4- [M + H]⁺ methoxymethoxy- carboxylic acid methyl ester 590.8 benzyl)-piperidin-4- dihydrochloride_(intermediate ylamino]-pyrimidine-4- C5) and 3-ethoxy-4-iodo-5- carboxylic acid methyl methoxymethoxy-benzaldehyde ester (intermediate D8) 115 514.03 2-chloro-6-[1-(3,5- 2-chloro-6-(piperidin-4- ISP diethoxy-4-pyrrol-1-yl- ylamino)-pyrimidine-4- [M + H]⁺ benzyl)-piperidin-4- carboxylic acid methyl ester 514.3 ylamino]-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3,5-diethoxy-4-pyrrol- ester 1-yl-benzaldehyde (intermediate D19) 116 483.39 2-chloro-6-[1-(2-chloro- 2-chloro-6-(piperidin-4- ESI 3,5-diethoxy-benzyl)- ylamino)-pyrimidine-4- [M − H]⁻ piperidin-4-ylamino]- carboxylic acid methyl ester 482.8 pyrimidine-4-carboxylic dihydrochloride_(intermediate acid methyl ester C5) and 2-chloro-3,5-diethoxy- benzaldehyde (intermediate D9) 117 479.92 2-chloro-6-[1-(3-ethoxy- 2-chloro-6-(piperidin-4- ESI 4-methoxy-5-nitro- ylamino)-pyrimidine-4- [M + H]⁺ benzyl)-piperidin-4- carboxylic acid methyl ester 477.8 ylamino]-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3-ethoxy-4-methoxy-5- ester nitro-benzaldehyde (intermediate D21) 118 433.94 2-chloro-6-[1-(3- 2-chloro-6-(piperidin-4- ESI ethylamino-4-methoxy- ylamino)-pyrimidine-4- [M + H]⁺ benzyl)-piperidin-4- carboxylic acid methyl ester 433.7 ylamino]-pyrimidine-4- dihydrochloride_(intermediate carboxylic acid methyl C5) and 3-ethylamino-4- ester methoxy-benzaldehyde (intermediate D22) 119 438.36 N-{2-chloro-6-[1-(4- N-[2-chloro-6-(piperidin-4- ISP chloro-3-ethoxy-benzyl)- ylamino)-pyrimidin-4-yl]- [M + H]⁺ piperidin-4-ylamino]- acetamide dihydrochloride 438.3 pyrimidin-4-yl}- (intermediate C6) and 4-chloro- acetamide 3-ethoxy-benzaldehyde (intermediate D2) 120 378.88 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3- yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-4-methyl- dihydrochloride (intermediate 379.3 benzyl)-piperidin-4-yl]- C7) and 3-ethoxy-4-methyl- amine benzaldehyde (intermediate D10) 121 382.84 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3- yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-4-fluoro-benzyl)- dihydrochloride (intermediate 383.1 piperidin-4-yl]-amine C7) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 122 399.30 [1-(4-chloro-3-ethoxy- (2-chloro-5-fluoro-pyrimidin-4- ISP benzyl)-piperidin-4-yl]- yl)-piperidin-4-yl-amine [M + H]⁺ (2-chloro-5-fluoro- dihydrochloride (intermediate 399.2 pyrimidin-4-yl)-amine C7) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 123 394.88 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3- yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-4-methoxy- dihydrochloride (intermediate 395.3 benzyl)-piperidin-4-yl]- C7) and 3-ethoxy-4-methoxy- amine benzaldehyde (commercially available) 124 408.90 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3,4- yl)-piperidin-4-yl-amine [M + H]⁺ diethoxy-benzyl)- dihydrochioride (intermediate 409.2 piperidin-4-yl]-amine C7) and 3,4-diethoxy- benzaldehyde (commercially available) 125 422.93 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3- yl)-piperidin-4-yl-amine [M + H]⁺ ethoxy-4-isopropoxy- dihydrochloride (intermediate 423.2 benzyl)-piperidin-4-yl]- C7) and 3-ethoxy-4-isopropoxy- amine benzaldehyde (commercially available) 126 408.90 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(4- yl)-piperidin-4-yl-amine [M + H]⁺ methoxy-3-propoxy- dihydrochloride (intermediate 409.2 benzyl)-piperidin-4-yl]- C7) and 4-methoxy-3-propoxy- amine benzaldehyde (intermediate D11) 127 412.87 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-{1-[3- yl)-piperidin-4-yl-amine [M + H]⁺ (2-fluoro-ethoxy)-4- dihydrochloride (intermediate 413.2 methoxy-benzyl]- C7) and 3-(2-fluoro-ethoxy)-4- piperidin-4-yl}-amine methoxy-benzaldehyde (intermediate D12) 128 448.85 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-{1-[4- yl)-piperidin-4-yl-amine [M + H]⁺ methoxy-3-(2,2,2- dihydrochloride (intermediate 449.1 trifluoro-ethoxy)- C7) and 4-methoxy-3-(2,2,2- benzyl]-piperidin-4-yl}- trifluoro-ethoxy)-benzaldehyde amine (intermediate D13) 129 406.89 [1-(3-allyloxy-4- (2-chloro-5-fluoro-pyrimidin-4- ISP methoxy-benzyl)- yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 407.3 chloro-5-fluoro- C7) and 3-allyloxy-4-methoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D14) 130 422.93 [1-(3-butoxy-4- (2-chloro-5-fluoro-pyrimidin-4- ISP methoxy-benzyl)- yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 423.2 chloro-5-fluoro- C7) and 3-butoxy-4-methoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D4) 131 422.93 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3- yl)-piperidin-4-yl-amine [M + H]⁺ isobutoxy-4-methoxy- dihydrochloride (intermediate 423.2 benzyl)-piperidin-4-yl]- C7) and 3-isobutoxy-4- amine methoxy-benzaldehyde (intermediate D15) 132 408.90 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3,5- yl)-piperidin-4-yl-amine [M + H]⁺ diethoxy-benzyl)- dihydrochloride (intermediate 409.3 piperidin-4-yl]-amine C7) and 3,5-diethoxy- benzaldehyde (intermediate D5) 133 436.96 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3,5- yl)-piperidin-4-yl-amine [M + H]⁺ diisopropoxy-benzyl)- dihydrochloride (intermediate 437.3 piperidin-4-yl]-amine C7) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 134 426.89 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3,5- yl)-piperidin-4-yl-amine [M + H]⁺ diethoxy-4-fluoro- dihydrochloride (intermediate 427.2 benzyl)-piperidin-4-yl]- C7) and 3,5-diethoxy-4-fluoro- amine benzaldehyde (intermediate D20) 135 443.35 [1-(4-chloro-3,5- (2-chloro-5-fluoro-pyrimidin-4- ISP diethoxy-benzyl)- yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 443.2 chloro-5-fluoro- C7) and 4-chloro-3,5-diethoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D17) 136 487.81 [1-(4-bromo-3,5- (2-chloro-5-fluoro-pyrimidin-4- ISP diethoxy-benzyl)- yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 487.1 chloro-5-fluoro- C7) and 4-bromo-3,5-diethoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D18) 137 473.98 (2-chloro-5-fluoro- (2-chloro-5-fluoro-pyrimidin-4- ISP pyrimidin-4-yl)-[1-(3,5- yl)-piperidin-4-yl-amine [M + H]⁺ diethoxy-4-pyrrol-1-yl- dihydrochloride (intermediate 474.2 benzyl)-piperidin-4-yl]- C7) and 3,5-diethoxy-4-pyrrol- amine 1-yl-benzaldehyde (intermediate D19) 138 443.35 [1-(2-chloro-3,5- (2-chloro-5-fluoro-pyrimidin-4- ISP diethoxy-benzyl)- yl)-piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(2- dihydrochloride (intermediate 443.2 chloro-5-fluoro- C7) and 2-chloro-3,5-diethoxy- pyrimidin-4-yl)-amine benzaldehyde (intermediate D9) 139 390.18 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ethoxy-4-methyl- amine dihydrochloride 391.2 benzyl)-piperidin-4-yl]- (intermediate C8) and 3-ethoxy- amine 4-methyl-benzaldehyde (intermediate D10) 140 394.16 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ethoxy-4-fluoro-benzyl)- amine dihydrochloride 395.2 piperidin-4-yl]-amine (intermediate C8) and 3-ethoxy- 4-fluoro-benzaldehyde (intermediate D1) 141 410.13 [1-(4-chloro-3-ethoxy- (2-chloro-5-methoxy- ESI benzyl)-piperidin-4-yl]- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ (2-chloro-5-methoxy- amine dihydrochloride 411.1 pyrimidin-4-yl)-amine (intermediate C8) and 4-chloro- 3-ethoxy-benzaldehyde (intermediate D2) 142 392.16 4-[4-(2-chloro-5- (2-chloro-5-methoxy- ESI methoxy-pyrimidin-4- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ylamino)-piperidin-1- amine dihydrochloride 393.2 ylmethyl]-2-ethoxy- (intermediate C8) and 3-ethoxy- phenol 4-hydroxy-benzaldehyde (commercially available) 143 406.18 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ethoxy-4-methoxy- amine dihydrochloride 407.2 benzyl)-piperidin-4-yl]- (intermediate C8) and 3-ethoxy- amine 4-methoxy-benzaldehyde (commercially available) 144 434.21 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ethoxy-4-isopropoxy- amine dihydrochloride 435.3 benzyl)-piperidin-4-yl]- (intermediate C8) and 3-ethoxy- amine 4-isopropoxy-benzaldehyde (commercially available) 145 462.24 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-{1-[3- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ethoxy-4-(1-ethyl- amine dihydrochloride 463.3 propoxy)-benzyl]- (intermediate C8) and 3-ethoxy- piperidin-4-yl}-amine 4-(1-ethyl-propoxy)- benzaldehyde (intermediate D3) 146 424.17 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-{1-[3- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ (2-fluoro-ethoxy)-4- amine dihydrochloride 425.2 methoxy-benzyl]- (intermediate C8) and 3-(2- piperidin-4-yl}-amine fluoro-ethoxy)-4-methoxy- benzaldehyde (intermediate D12) 147 418.18 [1-(3-allyloxy-4- (2-chloro-5-methoxy- ESI methoxy-benzyl)- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ piperidin-4-yl]-(2- amine dihydrochloride 419.3 chloro-5-methoxy- (intermediate C8) and 3- pyrimidin-4-yl)-amine allyloxy-4-methoxy- benzaldehyde (intermediate D14) 148 434.21 [1-(3-butoxy-4- (2-chloro-5-methoxy- ESI methoxy-benzyl)- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ piperidin-4-yl]-(2- amine dihydrochloride 435.3 chloro-5-methoxy- (intermediate C8) and 3-butoxy- pyrimidin-4-yl)-amine 4-methoxy-benzaldehyde (intermediate D4) 149 458.21 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(8- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ethoxy-2,2-dimethyl-2H- amine dihydrochloride 459.2 chromen-6-ylmethyl)- (intermediate C8) and 8-ethoxy- piperidin-4-yl]-amine 2,2-dimethyl-2H-chromene-6- carbaldehyde (intermediate D16) 150 420.19 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3,5- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ diethoxy-benzyl)- amine dihydrochloride 421.3 piperidin-4-yl]-amine (intermediate C8) and 3,5- diethoxy-benzaldehyde (intermediate D5) 151 448.22 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3,5- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ diisopropoxy-benzyl)- amine dihydrochloride 449.3 piperidin-4-yl]-amine (intermediate C8) and 3,5- diisopropoxy-benzaldehyde (intermediate D7) 152 406.18 3-[4-(2-chloro-5- (2-chloro-5-methoxy- ESI methoxy-pyrimidin-4- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ ylamino)-piperidin-1- amine dihydrochloride 407.2 ylmethyl]-5-isopropoxy- (intermediate C8) and 3- phenol hydroxy-5-isopropoxy- benzaldehyde (intermediate D6) 153 438.18 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3,5- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ diethoxy-4-fluoro- amine dihydrochloride 439.2 benzyl)-piperidin-4-yl]- (intermediate C8) and 3,5- amine diethoxy-4-fluoro-benzaldehyde (intermediate D20) 154 454.15 [1-(4-chloro-3,5- (2-chloro-5-methoxy- ESI diethoxy-benzyl)- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ piperidin-4-yl]-(2- amine dihydrochloride 455.2 chloro-5-methoxy- (intermediate C8) and 4-chloro- pyrimidin-4-yl)-amine 3,5-diethoxy-benzaldehyde (intermediate D17) 155 499.84 [1-(4-bromo-3,5- (2-chloro-5-methoxy- ESI diethoxy-benzyl)- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ piperidin-4-yl]-(2- amine dihydrochloride 499.2 chloro-5-methoxy- (intermediate C8) and 4-bromo- pyrimidin-4-yl)-amine 3,5-diethoxy-benzaldehyde (intermediate D18) 156 435.20 [1-(4-amino-3,5- (2-chloro-5-methoxy- ESI diethoxy-benzyl)- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ piperidin-4-yl]-(2- amine dihydrochloride 436.3 chloro-5-methoxy- (intermediate C8) and 4-amino- pyrimidin-4-yl)-amine 3,5-diethoxy-benzaldehyde (intermediate D23) 157 485.22 (2-chloro-5-methoxy- (2-chloro-5-methoxy- ESI pyrimidin-4-yl)-[1-(3,5- pyrimidin-4-yl)-piperidin-4-yl- [M − H]⁻ diethoxy-4-pyrrol-1-yl- amine dihydrochloride 484.3 benzyl)-piperidin-4-yl]- (intermediate C8) and 3,5- amine diethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate D19) 158 454.15 [1-(2-chloro-3,5- (2-chloro-5-methoxy- ESI diethoxy-benzyl)- pyrimidin-4-yl)-piperidin-4-yl- [M + H]⁺ piperidin-4-yl]-(2- amine dihydrochloride 455.2 chloro-5-methoxy- (intermediate C8) and 2-chloro- pyrimidin-4-yl)-amine 3,5-diethoxy-benzaldehyde (intermediate D9) 159 404.92 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine 405.4 fluoro-benzyl)-piperidin- dihydrochloride (intermediate 4-yl]-amine C9) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 160 421.37 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(4-chloro-3- piperidin-4-yl-amine 421.2 ethoxy-benzyl)- dihydrochloride (intermediate piperidin-4-yl]-amine C9) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 161 402.93 4-[4-(2-chloro-6,7- (2-chloro-6,7-dihydro-5H- ISP dihydro-5H- cyclopentapyrimidin-4-yl)- [M + H]⁺ cyclopentapyrimidin-4- piperidin-4-yl-amine 403.4 ylamino)-piperidin-1- dihydrochloride (intermediate ylmethyl]-2-ethoxy- C9) and 3-ethoxy-4-hydroxy- phenol benzaldehyde (commercially available) 162 416.96 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine 417.3 methoxy-benzyl)- dihydrochloride (intermediate piperidin-4-yl]-amine C9) and 3-ethoxy-4-methoxy- benzaldehyde (commercially available) 163 445.01 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine 445.3 isopropoxy-benzyl)- dihydrochloride (intermediate piperidin-4-yl]-amine C9) and 3-ethoxy-4-isopropoxy- benzaldehyde (commercially available) 164 473.06 ((2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-{1-[3-ethoxy-4-(1- piperidin-4-yl-amine 473.3 ethyl-propoxy)-benzyl]- dihydrochloride (intermediate piperidin-4-yl}-amine C9) and 3-ethoxy-4-(1-ethyl- propoxy)-benzaldehyde (intermediate D3) 165 481.02 methanesulfonic acid 4- (2-chloro-6,7-dihydro-5H- ISP [4-(2-chloro-6,7- cyclopentapyrimidin-4-yl)- [M + H]⁺ dihydro-5H- piperidin-4-yl-amine 481.2 cyclopentapyrimidin-4- dihydrochloride (intermediate ylamino)-piperidin-1- C9) and methanesulfonic acid 2- ylmethyl]-2-ethoxy- ethoxy-4-formyl-phenyl ester phenyl ester (intermediate D24) 166 434.95 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-{1-[3-(2-fluoro- piperidin-4-yl-amine 435.4 ethoxy)-4-methoxy- dihydrochloride (intermediate benzyl]-piperidin-4-yl}- C9) and 3-(2-fluoro-ethoxy)-4- amine methoxy-benzaldehyde (intermediate D12) 167 428.97 [1-(3-allyloxy-4- (2-chloro-6,7-dihydro-5H- ISP methoxy-benzyl)- cyclopentapyrimidin-4-yl)- [M + H]⁺ piperidin-4-yl]-(2- piperidin-4-yl-amine 429.3 chloro-6,7-dihydro-5H- dihydrochloride (intermediate cyclopentapyrimidin-4- C9) and 3-allyloxy-4-methoxy- yl)-amine benzaldehyde (intermediate D14) 168 445.01 [1-(3-butoxy-4- (2-chloro-6,7-dihydro-5H- ISP methoxy-benzyl)- cyclopentapyrimidin-4-yl)- [M + H]⁺ piperidin-4-yl]-(2- piperidin-4-yl-amine 445.3 chloro-6,7-dihydro-5H- dihydrochloride (intermediate cyclopentapyrimidin-4- C9) and 3-butoxy-4-methoxy- yl)-amine benzaldehyde (intermediate D4) 169 469.03 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(8-ethoxy-2,2- piperidin-4-yl-amine 469.3 dimethyl-2H-chromen- dihydrochloride (intermediate 6-ylmethyl)-piperidin-4- C9) and 8-ethoxy-2,2-dimethyl- yl]-amine 2H-chromene-6-carbaldehyde (intermediate D16) 170 430.98 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(3,5-diethoxy- piperidin-4-yl-amine 431.4 benzyl)-piperidin-4-yl]- dihydrochloride (intermediate amine C9) and 3,5-diethoxy- benzaldehyde (intermediate D5) 171 416.96 3-[4-(2-chloro-6,7- (2-chloro-6,7-dihydro-5H- ISP dihydro-5H- cyclopentapyrimidin-4-yl)- [M + H]⁺ cyclopentapyrimidin-4- piperidin-4-yl-amine 417.3 ylamino)-piperidin-1- dihydrochloride (intermediate ylmethyl]-5-isopropoxy- C9) and 3-hydroxy-5- phenol isopropoxy-benzaldehyde (intermediate D6) 172 459.04 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(3,5- piperidin-4-yl-amine 459.3 diisopropoxy-benzyl)- dihydrochloride (intermediate piperidin-4-yl]-amine C9) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 173 493.05 [1-(3-benzyloxy-5- (2-chloro-6,7-dihydro-5H- ISP ethoxy-benzyl)- cyclopentapyrimidin-4-yl)- [M + H]⁺ piperidin-4-yl]-(2- piperidin-4-yl-amine 493.3 chloro-6,7-dihydro-5H- dihydrochloride (intermediate cyclopentapyrimidin-4- C9) and 3-benzyloxy-5-ethoxy- yl)-amine benzaldehyde (intermediate D25) 174 448.97 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(3,5-diethoxy-4- piperidin-4-yl-amine 449.2 fluoro-benzyl)-piperidin- dihydrochloride (intermediate 4-yl]-amine C9) and 3,5-diethoxy-4-fluoro- benzaldehyde (intermediate D20) 175 496.06 (2-chloro-6,7-dihydro- (2-chloro-6,7-dihydro-5H- ISP 5H-cyclopentapyrimidin- cyclopentapyrimidin-4-yl)- [M + H]⁺ 4-yl)-[1-(3,5-diethoxy-4- piperidin-4-yl-amine 496.4 pyrrol-1-yl-benzyl)- dihydrochloride (intermediate piperidin-4-yl]-amine C9) and 3,5-diethoxy-4-pyrrol- 1-yl-benzaldehyde (intermediate D19) 176 465.43 [1-(2-chloro-3,5- (2-chloro-6,7-dihydro-5H- ISP diethoxy-benzyl)- cyclopentapyrimidin-4-yl)- [M + H]⁺ piperidin-4-yl]-(2- piperidin-4-yl-amine 465.2 chloro-6,7-dihydro-5H- dihydrochloride (intermediate cyclopentapyrimidin-4- C9) and 2-chloro-3,5-diethoxy- yl)-amine benzaldehyde (intermediate D9) 177 538.21 {2,4-dichloro-6-[1-(3,5- [2,4-dichloro-6-(piperidin-4- ESI diisopropoxy-benzyl)- ylamino)-pyrimidin-5-yl]-acetic [M + H]⁺ piperidin-4-ylamino]- acid ethyl ester dihydrochloride 539.3 pyrimidin-5-yl}-acetic (intermediate C10) and 3,5- acid ethyl ester diisopropoxy-benzaldehyde (intermediate D7) 178 528.17 {2,4-dichloro-6-[1-(3,5- [2,4-dichloro-6-(piperidin-4- ESI diethoxy-4-fluoro- ylamino)-pyrimidin-5-yl]-acetic [M + H]⁺ benzyl)-piperidin-4- acid ethyl ester dihydrochloride 529.3 ylamino]-pyrimidin-5- (intermediate C10) and 3,5- yl}-acetic acid ethyl ester diethoxy-4-fluoro-benzaldehyde (intermediate D20) 179 544.14 {2,4-dichloro-6-[1-(4- [2,4-dichloro-6-(piperidin-4- ESI chloro-3,5-diethoxy- ylamino)-pyrimidin-5-yl]-acetic [M + H]⁺ benzyl)-piperidin-4- acid ethyl ester dihydrochloride 547.3 ylamino]-pyrimidin-5- (intermediate C10) and 4- yl}-acetic acid ethyl ester chloro-3,5-diethoxy- benzaldehyde (intermediate D17) 180 525.19 {4-[1-(4-amino-3,5- [2,4-dichloro-6-(piperidin-4- ESI diethoxy-benzyl)- ylamino)-pyrimidin-5-yl]-acetic [M − H]⁻ piperidin-4-ylamino]- acid ethyl ester dihydrochloride 524.3 2,6-dichloro-pyrimidin- (intermediate C10) and 4- 5-yl}-acetic acid ethyl amino-3,5-diethoxy- ester benzaldehyde (intermediate D23) 181 575.21 {2,4-dichloro-6-[1-(3,5- [2,4-dichloro-6-(piperidin-4- ESI diethoxy-4-pyrrol-1-yl- ylamino)-pyrimidin-5-yl]-acetic [M + H]⁺ benzyl)-piperidin-4- acid ethyl ester dihydrochloride 576.3 ylamino]-pyrimidin-5- (intermediate C10) and 3,5- yl}-acetic acid ethyl ester diethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate D19) 182 429.78 [1-(3-ethoxy-4-methyl- piperidin-4-yl-(2,5,6-trichloro- ISP benzyl)-piperidin-4-yl]- pyrimidin-4-yl)-amine [M + H]⁺ (2,5,6-trichloro- dihydrochloride (intermediate 429.2 pyrimidin-4-yl)-amine C11) and 3-ethoxy-4-methyl- benzaldehyde (intermediate D10) 183 450.20 [1-(4-chloro-3-ethoxy- piperidin-4-yl-(2,5,6-trichloro- ISP benzyl)-piperidin-4-yl]- pyrimidin-4-yl)-amine [M + H]⁺ (2,5,6-trichloro- dihydrochloride (intermediate 451.0 pyrimidin-4-yl)-amine C11) and 4-chloro-3-ethoxy- benzaldehyde (intermediate D2) 184 445.78 [1-(3-ethoxy-4-methoxy- piperidin-4-yl-(2,5,6-trichloro- ISP benzyl)-piperidin-4-yl]- pyrimidin-4-yl)-amine [M + H]⁺ (2,5,6-trichloro- dihydrochloride (intermediate 447.1 pyrimidin-4-yl)-amine C11) and 3-ethoxy-4-methoxy- benzaldehyde (commercially available) 185 463.77 {1-[3-(2-fluoro-ethoxy)- piperidin-4-yl-(2,5,6-trichloro- ISP 4-methoxy-benzyl]- pyrimidin-4-yl)-amine [M + H]⁺ piperidin-4-yl}-(2,5,6- dihydrochloride (intermediate 465.1 trichloro-pyrimidin-4- C11) and 3-(2-fluoro-ethoxy)-4- yl)-amine methoxy-benzaldehyde (intermediate D12) 186 473.83 [1-(3-isobutoxy-4- piperidin-4-yl-(2,5,6-trichloro- ISP methoxy-benzyl)- pyrimidin-4-yl)-amine [M + H]⁺ piperidin-4-yl]-(2,5,6- dihydrochloride (intermediate 473.1 trichloro-pyrimidin-4- C11) and 3-isobutoxy-4- yl)-amine methoxy-benzaldehyde (intermediate D15) 187 487.86 [1-(3,5-diisopropoxy- piperidin-4-yl-(2,5,6-trichloro- ISP benzyl)-piperidin-4-yl]- pyrimidin-4-yl)-amine [M + H]⁺ (2,5,6-trichloro- dihydrochloride (intermediate 487.2 pyrimidin-4-yl)-amine C11) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 188 494.25 [1-(4-chloro-3,5- piperidin-4-yl-(2,5,6-trichloro- ISP diethoxy-benzyl)- pyrimidin-4-yl)-amine [M + H]⁺ piperidin-4-yl]-(2,5,6- dihydrochloride (intermediate 495.2 trichloro-pyrimidin-4- C11) and 4-chloro-3,5-diethoxy- yl)-amine benzaldehyde (intermediate D17) 189 524.88 [1-(3,5-diethoxy-4- piperidin-4-yl-(2,5,6-trichloro- ISP pyrrol-1-yl-benzyl)- pyrimidin-4-yl)-amine [M + H]⁺ piperidin-4-yl]-(2,5,6- dihydrochloride (intermediate 524.2 trichloro-pyrimidin-4- C11) and 3,5-diethoxy-4-pyrrol- yl)-amine 1-yl-benzaldehyde (intermediate D19) 190 410.95 (7-chloro-quinazolin-4- (7-chloro-quinazolin-4-yl)- ESI yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ methyl-benzyl)- dihydrochloride (intermediate 410.7 piperidin-4-yl]-amine C12) and 3-ethoxy-4-methyl- benzaldehyde (intermediate D10) 191 414.91 (7-chloro-quinazolin-4- (7-chloro-quinazolin-4-yl)- ESI yl)-[1-(3-ethoxy-4- piperidin-4-yl-amine [M + H]⁺ fluoro-benzyl)-piperidin- dihydrochloride (intermediate 414.6 4-yl]-amine C12) and 3-ethoxy-4-fluoro- benzaldehyde (intermediate D1) 192 412.92 4-[4-(7-chloro- (7-chloro-quinazolin-4-yl)- ESI quinazolin-4-ylamino)- piperidin-4-yl-amine [M + H]⁺ piperidin-1-ylmethyl]-2- dihydrochloride (intermediate 412.6 ethoxy-phenol C12) and 3-ethoxy-4-hydroxy- benzaldehyde (commercially available) 193 440.97 (7-chloro-quinazolin-4- (7-chloro-quinazolin-4-yl)- ESI yl)-[1-(3,5-diethoxy- piperidin-4-yl-amine [M + H]⁺ benzyl)-piperidin-4-yl]- dihydrochloride (intermediate 440.7 amine C12) and 3,5-diethoxy- benzaldehyde (intermediate D5) 194 469.03 (7-chloro-quinazolin-4- (7-chloro-quinazolin-4-yl)- ESI yl)-[1-(3,5-diisopropoxy- piperidin-4-yl-amine [M + H]⁺ benzyl)-piperidin-4-yl]- dihydrochloride (intermediate 468.7 amine C12) and 3,5-diisopropoxy- benzaldehyde (intermediate D7) 195 458.96 (7-chloro-quinazolin-4- (7-chloro-quinazolin-4-yl)- ESI yl)-[1-(3,5-diethoxy-4- piperidin-4-yl-amine [M + H]⁺ fluoro-benzyl)-piperidin- dihydrochloride (intermediate 458.7 4-yl]-amine C12) and 3,5-diethoxy-4-fluoro- benzaldehyde (intermediate D20) 196 475.42 [1-(4-chloro-3,5- (7-chloro-quinazolin-4-yl)- ESI diethoxy-benzyl)- piperidin-4-yl-amine [M + H]⁺ piperidin-4-yl]-(7- dihydrochloride (intermediate 475.4 chloro-quinazolin-4-yl)- C12) and 4-chloro-3,5-diethoxy- amine benzaldehyde (intermediate D17) 197 455.99 [1-(4-amino-3,5- (7-chloro-quinazolin-4-yl)- ESI diethoxy-benzyl)- piperidin-4-yl-amine [M − H]⁻ piperidin-4-yl]-(7- dihydrochloride (intermediate 453.7 chloro-quinazolin-4-yl)- C12) and 4-amino-3,5-diethoxy- amine benzaldehyde (intermediate D23) 198 506.05 (7-chloro-quinazolin-4- (7-chloro-quinazolin-4-yl)- ESI yl)-[1-(3,5-diethoxy-4- piperidin-4-yl-amine [M − H]⁻ pyrrol-1-yl-benzyl)- dihydrochloride (intermediate 505.8 piperidin-4-yl]-amine C12) and 3,5-diethoxy-4-pyrrol- 1-yl-benzaldehyde (intermediate D19) 199 474.97 (2-chloro-6,7- (2-chloro-6,7-dimethoxy- ISP dimethoxy-quinazolin-4- quinazolin-4-yl)-piperidin-4-yl- [M + H]⁺ yl)-[1-(3-ethoxy-4- amine dihydrochloride 475.1 fluoro-benzyl)-piperidin- (intermediate C13) and 3- 4-yl]-amine ethoxy-4-fluoro-benzaldehyde (intermediate D1) 200 491.42 (2-chloro-6,7- (2-chloro-6,7-dimethoxy- ISP dimethoxy-quinazolin-4- quinazolin-4-yl)-piperidin-4-yl- [M + H]⁺ yl)-[1-(4-chloro-3- amine dihydrochloride 491.1 ethoxy-benzyl)- (intermediate C13) and 4- piperidin-4-yl]-amine chloro-3-ethoxy-benzaldehyde (intermediate D2) 201 529.08 (2-chloro-6,7- (2-chloro-6,7-dimethoxy- ISP dimethoxy-quinazolin-4- quinazolin-4-yl)-piperidin-4-yl- [M + H]⁺ yl)-[1-(3,5-diisopropoxy- amine dihydrochloride 529.2 benzyl)-piperidin-4-yl]- (intermediate C13) and 3,5- amine diisopropoxy-benzaldehyde (intermediate D7) 202 519.02 (2-chloro-6,7- (2-chloro-6,7-dimethoxy- ISP dimethoxy-quinazolin-4- quinazolin-4-yl)-piperidin-4-yl- [M + H]⁺ yl)-[1-(3,5-diethoxy-4- amine dihydrochloride 519.3 fluoro-benzyl)-piperidin- (intermediate C13) and 3,5- 4-yl]-amine diethoxy-4-fluoro-benzaldehyde (intermediate D20) 203 566.11 (2-chloro-6,7- (2-chloro-6,7-dimethoxy- ISP dimethoxy-quinazolin-4- quinazolin-4-yl)-piperidin-4-yl- [M + H]⁺ yl)-[1-(3,5-diethoxy-4- amine dihydrochloride 566.3 pyrrol-1-yl-benzyl)- (intermediate C13) and 3,5- piperidin-4-yl]-amine diethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate D19) 204 366.47 [1-(3-ethoxy-4-methyl- piperidin-4-yl-(9H-purin-6-yl)- ISP benzyl)-piperidin-4-yl]- amine dihydrochloride [M + H]⁺ (9H-purin-6-yl)-amine (intermediate C14) and 3- 367.2 ethoxy-4-methyl-benzaldehyde (intermediate D10) 205 386.89 [1-(4-chloro-3-ethoxy- piperidin-4-yl-(9H-purin-6-yl)- ISP benzyl)-piperidin-4-yl]- amine dihydrochloride [M + H]⁺ (9H-purin-6-yl)-amine (intermediate C14) and 4- 387.2 chloro-3-ethoxy-benzaldehyde (intermediate D2) 206 368.44 2-ethoxy-4-[4-(9H- piperidin-4-yl-(9H-purin-6-yl)- ISP purin-6-ylamino)- amine dihydrochloride [M + H]⁺ piperidin-1-ylmethyl]- (intermediate C14) and 3- 369.3 phenol ethoxy-4-hydroxy-benzaldehyde (commercially available) 207 382.47 [1-(3-ethoxy-4-methoxy- piperidin-4-yl-(9H-purin-6-yl)- ISP benzyl)-piperidin-4-yl]- amine dihydrochloride [M + H]⁺ (9H-purin-6-yl)-amine (intermediate C14) and 3- 383.2 ethoxy-4-methoxy-benzaldehyde (commercially available) 208 410.52 [1-(3-ethoxy-4- piperidin-4-yl-(9H-purin-6-yl)- ISP isopropoxy-benzyl)- amine dihydrochloride [M + H]⁺ piperidin-4-yl]-(9H- (intermediate C14) and 3- 411.4 purin-6-yl)-amine ethoxy-4-isopropoxy- benzaldehyde (commercially available) 209 396.49 [1-(4-methoxy-3- piperidin-4-yl-(9H-purin-6-yl)- ISP propoxy-benzyl)- amine dihydrochloride [M + H]⁺ piperidin-4-yl]-(9H- (intermediate C14) and 4- 397.3 purin-6-yl)-amine methoxy-3-propoxy- benzaldehyde (intermediate D11) 210 400.46 {1-[3-(2-fluoro-ethoxy)- piperidin-4-yl-(9H-purin-6-yl)- ISP 4-methoxy-benzyl]- amine dihydrochloride [M + H]⁺ piperidin-4-yl}-(9H- (intermediate C14) and 3-(2- 401.3 purin-6-yl)-amine fluoro-ethoxy)-4-methoxy- benzaldehyde (intermediate D12) 211 410.52 [1-(3-butoxy-4- piperidin-4-yl-(9H-purin-6-yl)- ISP methoxy-benzyl)- amine dihydrochloride [M + H]⁺ piperidin-4-yl]-(9H- (intermediate C14) and 3- 411.4 purin-6-yl)-amine butoxy-4-methoxy- benzaldehyde (intermediate D4) 212 410.52 [1-(3-isobutoxy-4- piperidin-4-yl-(9H-purin-6-yl)- ISP methoxy-benzyl)- amine dihydrochloride [M + H]⁺ piperidin-4-yl]-(9H- (intermediate C14) and 3- 411.4 purin-6-yl)-amine isobutoxy-4-methoxy- benzaldehyde (intermediate D15) 213 434.54 [1-(8-ethoxy-2,2- piperidin-4-yl-(9H-purin-6-yl)- ISP dimethyl-2H-chromen- amine dihydrochloride [M + H]⁺ 6-ylmethyl)-piperidin-4- (intermediate C14) and 8- 435.4 yl]-(9H-purin-6-yl)- ethoxy-2,2-dimethyl-2H- amine chromene-6-carbaldehyde (intermediate D16) 214 424.55 [1-(3,5-diisopropoxy- piperidin-4-yl-(9H-purin-6-yl)- ISP benzyl)-piperidin-4-yl]- amine dihydrochloride [M + H]⁺ (9H-purin-6-yl)-amine (intermediate C14) and 3,5- 425.4 diisopropoxy-benzaldehyde (intermediate D7) 215 430.94 [1-(4-chloro-3,5- piperidin-4-yl-(9H-purin-6-yl)- ISP diethoxy-benzyl)- amine dihydrochloride [M + H]⁺ piperidin-4-yl]-(9H- (intermediate C14) and 4- 431.3 purin-6-yl)-amine chloro-3,5-diethoxy- benzaldehyde (intermediate D17) 216 461.57 [1-(3,5-diethoxy-4- piperidin-4-yl-(9H-purin-6-yl)- ISP pyrrol-1-yl-benzyl)- amine dihydrochloride [M + H]⁺ piperidin-4-yl]-(9H- (intermediate C14) and 3,5- 462.4 purin-6-yl)-amine diethoxy-4-pyrrol-1-yl- benzaldehyde (intermediate D19)

Example 217 6-[1-(4-Chloro-3-ethoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-2,4-dicarboxylic acid

To a solution of 2-chloro-6-(piperidin-4-ylamino)-pyrimidine-4-carboxylic acid methyl ester dihydrochloride (51.6 mg, 0.15 mmol, 1.0 equiv; intermediate C5) in ethanol (2 mL) was added 4-chloro-3-ethoxy-benzaldehyde (33.2 mg, 0.18 mmol, 1.2 equiv; intermediate D2), acetic acid (27.0 mg, 0.45 mmol, 3.0 equiv) and N-ethyl diisopropylamine (58.3 mg, 0.45 mmol, 3.0 equiv) and the reaction mixture stirred at 55° C. After 1 h, sodium cyanoborohydride (47.1 mg, 0.75 mmol, 5.0 equiv), dissolved in ethanol (0.5 mL), was added and the mixture stirred at 55° C. After 8 h, a 10 M NaOH solution (0.75 mL) was added and heating continued at 55° C. over night. Removal of the solvent under reduced pressure and purification by preparative HPLC on reversed phase eluting with a gradient of acetonitrile/water provided 2.5 mg (4%) of the title compound. MS (ESI): 434.4 [M+H]⁺.

Example A

Film coated tablets containing the following ingredients can be manufactured in a conventional manner:

Ingredients Per tablet Kernel: Compound of formula I 10.0 mg 200.0 mg  Microcrystalline cellulose 23.5 mg 43.5 mg  Lactose hydrous 60.0 mg 70.0 mg  Povidone K30 12.5 mg 15.0 mg  Sodium starch glycolate 12.5 mg 17.0 mg  Magnesium stearate  1.5 mg 4.5 mg (Kernel Weight) 120.0 mg  350.0 mg  Film Coat: Hydroxypropyl methyl cellulose  3.5 mg 7.0 mg Polyethylene glycol 6000  0.8 mg 1.6 mg Talc  1.3 mg 2.6 mg Iron oxide (yellow)  0.8 mg 1.6 mg Titanium dioxide  0.8 mg 1.6 mg

The active ingredient is sieved and mixed with microcrystalline cellulose and the mixture is granulated with a solution of polyvinylpyrrolidone in water. The granulate is mixed with sodium starch glycolate and magnesium stearate and compressed to yield kernels of 120 or 350 mg respectively. The kernels are lacquered with an aqueous solution/suspension of the above mentioned film coat.

Example B

Capsules containing the following ingredients can be manufactured in a conventional manner:

Ingredients Per capsule Compound of formula I 25.0 mg Lactose 150.0 mg  Maize starch 20.0 mg Talc  5.0 mg

The components are sieved and mixed and filled into capsules of size 2.

Example C

Injection solutions can have the following composition:

Compound of formula I 3.0 mg Gelatine 150.0 mg Phenol 4.7 mg Sodium carbonate to obtain a final pH of 7 Water for injection solutions ad 1.0 mL

Example D

Soft gelatin capsules containing the following ingredients can be manufactured in a conventional manner:

Capsule contents Compound of formula I 5.0 mg Yellow wax 8.0 mg Hydrogenated Soya bean oil 8.0 mg Partially hydrogenated plant oils 34.0 mg  Soya bean oil 110.0 mg  Weight of capsule contents 165.0 mg  Gelatin capsule Gelatin 75.0 mg  Glycerol 85% 32.0 mg  Karion 83 8.0 mg (dry matter) Titanium dioxide 0.4 mg Iron oxide yellow 1.1 mg

The active ingredient is dissolved in a warm melting of the other ingredients and the mixture is filled into soft gelatin capsules of appropriate size. The filled soft gelatin capsules are treated according to the usual procedures.

Example E

Sachets containing the following ingredients can be manufactured in a conventional manner:

Compound of formula I 50.0 mg Lactose, fine powder 1015.0 mg  Microcrystalline cellulose (AVICEL PH 102) 1400.0 mg  Sodium carboxymethyl cellulose 14.0 mg Polyvinylpyrrolidone K 30 10.0 mg Magnesium stearate 10.0 mg Flavoring additives  1.0 mg

The active ingredient is mixed with lactose, microcrystalline cellulose and sodium carboxymethyl cellulose and granulated with a mixture of polyvinylpyrrolidone in water. The granulate is mixed with magnesium stearate and the flavoring additives and filled into sachets.

It is to be understood that the invention is not limited to the particular embodiments of the invention described above, as variations of the particular embodiments may be made and still fall within the scope of the appended claims. 

1. A compound of formula I:

wherein A is —O— or —NH—; R¹ is selected from the group consisting of hydrogen, C₁₋₇-alkoxy and halogen; R² is selected from the group consisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl, C₁₋₇-alkoxy-C₁₋₇-alkyl, and benzyl; R³ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, C₂₋₇-alkenyloxy, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, —O—C₃₋₇-cycloalkyl, halogen, halogen-C₁₋₇-alkyl, —NR⁶R⁷, wherein R⁶ and R⁷ independently from each other are hydrogen or C₁₋₇-alkyl, —O—SO₂—R⁸, wherein R⁸ is C₁₋₇-alkyl, and pyrrolyl; R⁴ is selected from the group consisting of hydrogen, hydroxy, C₁₋₇-alkoxy, amino, nitro, hydroxy-C₁₋₇-alkoxy, C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl; or R³ and R⁴ are bonded to each other to form a ring together with the carbon atoms they are attached to and R³ and R⁴ together are —O—C(CH₃)₂—CH═CH—; R⁵ is selected from the group consisting of hydrogen, halogen and C₁₋₇-alkoxy; G is selected from the groups

wherein R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR¹⁷, wherein R'⁷ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR¹⁸, wherein R¹⁸ is hydrogen or C₁₋₇-alkyl; R¹⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, —C(O)—OR¹⁹, wherein R¹⁹ is hydrogen or C₁₋₇-alkyl, and —NR²⁰R²¹, wherein R²⁰ is hydrogen or C₁₋₇-alkyl and R²¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl and C₁₋₇-alkylcarbonyl, or wherein R²⁰ and R²¹ together with the nitrogen atom they are attached to form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring; R¹¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, amino, —(CH₂)_(m)—C(O)—OR²², wherein m is 0 or 1 and R²² is hydrogen or C₁₋₇-alkyl, phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl, and —(CH₂)_(n)-phenyl, wherein n is 0 or 1 and phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl; R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR²³, wherein R²³ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR²⁴, wherein R²⁴ is hydrogen or C₁₋₇-alkyl; R¹³, R¹⁴, R¹⁵ and R¹⁶ independently from each other are selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, hydroxy, and C₁₋₇-alkoxy; and pharmaceutically acceptable salts thereof.
 2. The compound according to claim 1, wherein A is O.
 3. The compound according to claim 1, wherein R¹ is hydrogen or halogen.
 4. The compound according to claim 1, wherein R² is selected from the group consisting of C₂₋₇-alkyl, C₂₋₇-alkenyl, halogen-C₁₋₇-alkyl and C₁₋₇-alkoxy-C₁₋₇-alkyl.
 5. The compound according to claim 1, wherein R² is selected from the group consisting of ethyl, propyl, isopropyl, allyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, butyl and isobutyl.
 6. The compound according to claim 1, wherein R³ is selected from the group consisting of is selected from the group consisting of hydrogen, C₁₋₇-alkyl, hydroxy, C₁₋₇-alkoxy, halogen, —NR⁶R⁷, wherein R⁶ and R⁷ independently from each other are hydrogen or C₁₋₇-alkyl, —O—SO₂—R⁸, wherein R⁸ is C₁₋₇-alkyl, and pyrrolyl.
 7. The compound according to claim 1, wherein R³ is hydrogen or halogen.
 8. The compound according to claim 1, wherein R³ is halogen.
 9. The compound according to claim 1, wherein R⁴ is selected from the group consisting of hydrogen, hydroxy, C₁₋₇-alkoxy, nitro, C₁₋₇-alkoxy-C₁₋₇-alkoxy, and —O-benzyl.
 10. The compound according to claim 1, wherein R³ and R⁴ are bonded to each other to form a ring together with the carbon atoms they are attached to and R³ and R⁴ together are —O—C(CH₃)₂—CH═CH—.
 11. The compound according to claim 1, wherein R⁵ is hydrogen or halogen.
 12. The compound according to claim 1, wherein G is

and wherein R⁹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR¹⁷, wherein R'⁷ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR¹⁸, wherein R¹⁸ is hydrogen or C₁₋₇-alkyl; R¹⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, —C(O)—OR¹⁹, wherein R¹⁹ is hydrogen or C₁₋₇-alkyl, and —NR²⁰R²¹, wherein R²⁰ is hydrogen or C₁₋₇-alkyl and R²¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl and C₁₋₇-alkylcarbonyl, or wherein R²⁰ and R²¹ together with the nitrogen atom they are attached to form a 3-, 4-, 5-, 6- or 7-membered heterocyclic ring; R¹¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen, halogen-C₁₋₇-alkyl, amino, —(CH₂)_(m)—C(O)—OR²², wherein m is 0 or 1 and R²² is hydrogen or C₁₋₇-alkyl, phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl, and —(CH₂)_(n)-phenyl, wherein n is 0 or 1 and phenyl is unsubstituted or substituted by one to three groups selected from the group consisting of C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and halogen-C₁₋₇-alkyl.
 13. The compound according to claim 1, wherein R⁹ is hydrogen or halogen; R¹⁰ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and —C(O)—OR¹⁹, wherein R¹⁹ is hydrogen or C₁₋₇-alkyl; R¹¹ is selected from the group consisting of hydrogen, C₁₋₇-alkyl, C₁₋₇-alkoxy, halogen and phenyloxy, wherein phenyl is unsubstituted or substituted by one to three groups selected from C₁₋₇-alkyl and C₁₋₇-alkoxy.
 14. The compound according to claim 1, wherein G is

and wherein R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR²³, wherein R²³ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR²⁴, wherein R²⁴ is hydrogen or C₁₋₇-alkyl; R¹³, R¹⁴, R¹⁵ and R¹⁶ independently from each other are selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, hydroxy, and C₁₋₇-alkoxy.
 15. The compound according to claim 1, wherein R¹² is halogen.
 16. The compound according to claim 1, wherein G is selected from the group consisting of

and wherein R¹² is selected from the group consisting of hydrogen, C₁₋₇-alkyl, halogen, halogen-C₁₋₇-alkyl, amino, phenyl, —OR²³, wherein R²³ is hydrogen or C₁₋₇-alkyl, and —C(O)—OR²⁴, wherein R²⁴ is hydrogen or C₁₋₇-alkyl.
 17. The compound according to claim 16, wherein R¹² is halogen.
 18. The compound according to claim 1, selected from the group consisting of [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-pyrimidin-4-yl)-amine, [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(7-chloro-quinazolin-4-yl)-amine, (6-chloro-5-o-tolyloxy-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, [6-chloro-5-(2-methoxy-phenoxy)-pyrimidin-4-yl]-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine (2-chloro-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, [1-(4-chloro-3-ethoxy-benzyl)-piperidin-4-yl]-(2-chloro-6-methyl-pyrimidin-4-yl)-amine, (2-chloro-6-methyl-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2,6-dichloro-pyrimidin-4-yl)-amine, 2-chloro-6-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-ylamino]-pyrimidine-4-carboxylic acid methyl ester, [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-fluoro-pyrimidin-4-yl)-amine, (2-chloro-5-methoxy-pyrimidin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, [1-(4-chloro-3,5-diethoxy-benzyl)-piperidin-4-yl]-(2-chloro-5-methoxy-pyrimidin-4-yl)-amine, (2-chloro-6,7-dihydro-5H-cyclopentapyrimidin-4-yl)-[1-(3,5-diethoxy-4-fluoro-benzyl)-piperidin-4-yl]-amine, (7-chloro-quinazolin-4-yl)-[1-(3,5-diisopropoxy-benzyl)-piperidin-4-yl]-amine, and pharmaceutically acceptable salts thereof.
 19. A process for the manufacture of a compound according to claim 1, comprising the steps of: a) reacting a compound of the general formula G-X  II wherein G is as defined in claim 1 and X is halogen, with a compound of the formula

wherein A and R¹ to R⁵ are as defined in claim 1, to obtain a compound of the formula

and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt; or, alternatively, b) reacting a compound of the general formula

wherein G is as defined in claim 1, with an aldehyde of the formula

wherein A and R¹ to R⁵ are as defined in claim 1, by employing a reducing agent to obtain a compound of the formula

and, if desired, converting the compound of formula I into a pharmaceutically acceptable salt.
 20. A pharmaceutical composition, comprising a therapeutically effective amount of a compound according to claim 1 as well as a pharmaceutically acceptable carrier and/or adjuvant. 